{"gene":"F11R","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2002,"finding":"JAM-1/F11R is a ligand for the β2 integrin LFA-1; the membrane-proximal Ig-like domain 2 of JAM-1 is required for LFA-1-mediated leukocyte adhesion and transendothelial migration under static and flow conditions.","method":"Transfection of JAM-1 into cells combined with LFA-1-dependent adhesion assays under static and physiological flow; domain deletion experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays with domain mutants, replicated across T cells and neutrophils in multiple conditions","pmids":["11812992"],"is_preprint":false},{"year":2002,"finding":"F11R/JAM-A mediates platelet adhesion to cytokine-inflamed endothelial cells through homophilic interactions; peptides spanning the N-terminal region and first Ig-fold of F11R inhibit this adhesion, identifying those regions as the adhesive interface.","method":"Platelet adhesion assays to immobilized recombinant sF11R and to cytokine-stimulated HUVEC; inhibition by recombinant sF11R and domain-specific peptides","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal inhibition approaches (soluble protein, peptides), replicated across platelet-endothelial cell adhesion assays","pmids":["12428104"],"is_preprint":false},{"year":2002,"finding":"Two regions of F11R — the N-terminal sequence (S1–C23) and the K70–C82 sequence in the first Ig-fold — are critical for M.Ab.F11-induced platelet aggregation, adhesion, and potentiation; a soluble recombinant sF11R completely inhibits these responses.","method":"Peptide inhibition studies of M.Ab.F11-mediated platelet aggregation, adhesion, and potentiation; 3D structure modeling of the extracellular domain","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide inhibition assays with domain mapping, single lab, multiple functional readouts","pmids":["12008956"],"is_preprint":false},{"year":2003,"finding":"JAM-1/A and integrin αvβ3 form a complex in quiescent endothelial cells; bFGF treatment causes JAM-1 to redistribute to the cell surface and dissociates the JAM-1/αvβ3 complex, enabling MAP kinase activation required for bFGF-induced angiogenesis. Mutation of the JAM-1 cytoplasmic domain blocks bFGF-induced MAP kinase activation and tube formation.","method":"Co-immunoprecipitation; cytoplasmic domain mutagenesis; endothelial cell morphology, proliferation, and tube formation assays; antibody blockade","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP identifying complex, cytoplasmic domain mutagenesis with defined phenotypic readouts, multiple orthogonal assays in a single study","pmids":["12750158"],"is_preprint":false},{"year":2004,"finding":"F11R/JAM-A in platelets signals through phosphoinositide-3-kinase activation; M.Ab.F11 crosslinking of F11R with FcγRII induces actin filament assembly, phosphorylation of the 32 and 35 kDa F11R forms, F11R dimerization, and association of F11R with integrin GPIIIa and CD9.","method":"Co-immunoprecipitation; phosphorylation assays; wortmannin inhibition; platelet aggregation and spreading assays","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating complex with GPIIIa/CD9, phosphorylation assays, PI3K inhibitor experiments; single lab","pmids":["15344881"],"is_preprint":false},{"year":2007,"finding":"JAM-A deficiency in vivo (knockout mice and neutralizing antibody) specifically reduces leukocyte transmigration (but not adhesion) in response to IL-1β or ischemia/reperfusion stimuli, but not to LTB4 or PAF; endothelial-cell JAM-A is the relevant pool; JAM-A and PECAM-1 act sequentially in this transmigration process.","method":"Intravital microscopy in JAM-A KO mice and antibody-treated mice; leukocyte transfer experiments; dual blockade/deletion epistasis analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus antibody blockade, leukocyte transfer epistasis, replicated across multiple inflammatory stimuli","pmids":["17505016"],"is_preprint":false},{"year":2007,"finding":"JAM-A deficiency increases intestinal epithelial permeability in vivo and in vitro, associated with increased expression of claudin-10 and claudin-15 in colonic mucosa and JAM-A siRNA-treated cells.","method":"JAM-A knockout mice; dextran flux and transepithelial resistance assays; siRNA knockdown in epithelial cells; Western blot for claudin isoforms","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus siRNA in matched in vitro/in vivo model with multiple barrier readouts","pmids":["18039951"],"is_preprint":false},{"year":2007,"finding":"JAM-A is present on the plasma membrane of sperm flagella; deletion of Jam-A causes flagellar ultrastructural defects and significantly impairs progressive and hyperactivated sperm motility before and after capacitation.","method":"Immunolocalization; gene-trap JAM-A knockout mice; sperm motility analysis; electron microscopy of flagellar ultrastructure","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined ultrastructural and motility phenotype, direct localization by immunofluorescence; single lab","pmids":["18022613"],"is_preprint":false},{"year":2009,"finding":"JAM-A on neutrophils is required cell-autonomously for chemotaxis: it concentrates at the leading edge and uropod, is internalized with β1 integrin into endosomal vesicles, and is required for correct internalization and recycling of β1 integrins during migration; clustering of β1 integrin co-clusters JAM-A but not vice versa.","method":"JAM-A null neutrophil chemotaxis assays in vivo and in vitro; co-clustering experiments; BAPTA-AM inhibition of integrin internalization; intravital microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null phenotype combined with pharmacological rescue and co-clustering experiments; multiple orthogonal methods","pmids":["19118219"],"is_preprint":false},{"year":2009,"finding":"LFA-1 binding to domain 2 of JAM-A destabilizes the JAM-A homophilic interaction; the second Ig domain of JAM-A stabilizes the homophilic interaction, and LFA-1 binding to this domain cancels this stabilization; the LFA-1/JAM-A heterophilic interaction is stronger than the JAM-A homophilic interaction.","method":"Competitive binding assays; atomic force microscopy adhesion measurements with domain deletion mutants and LFA-1 inserted domain","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative biophysical (AFM) plus domain deletion mutants; single lab but rigorous mechanistic characterization","pmids":["18849408"],"is_preprint":false},{"year":2009,"finding":"ICAM-2, JAM-A, and PECAM-1 act sequentially to mediate neutrophil transendothelial migration in a stimulus-dependent manner; when direct neutrophil stimulation is blocked, TNF-α-induced transmigration becomes dependent on all three endothelial molecules.","method":"Cell-transfer technique with TNFR-deficient leukocytes; fluorescence intravital microscopy in ICAM-2-/-, JAM-A-/-, PECAM-1-/- mice; analysis of arrest sites","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic triple-KO epistasis, intravital microscopy, cell-transfer approach demonstrating sequential action","pmids":["19211506"],"is_preprint":false},{"year":2011,"finding":"JAM-A restricts intestinal epithelial cell proliferation in a dimerization-dependent manner by inhibiting Akt-dependent β-catenin activation; JAM-A-deficient IECs show enhanced β-catenin-dependent transcription, and Akt inhibition reverses colonic crypt hyperproliferation in JAM-A KO mice.","method":"JAM-A KO mice; transgenic β-catenin/TCF reporter mice; Akt inhibitor treatment; in vitro dimerization-deficient mutant expression","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary in vivo and in vitro epistasis with pharmacological and genetic rescue","pmids":["21372850"],"is_preprint":false},{"year":2012,"finding":"aPKC directly interacts with JAM-A independent of PAR-3 and phosphorylates JAM-A at Ser285; this phosphorylation is required for maturation of cell-cell contacts, tight junction formation, and single lumen specification. Protein phosphatase 2A dephosphorylates JAM-A at Ser285, antagonizing aPKC.","method":"Direct binding assays (aPKC–JAM-A); phospho-specific antibodies; non-phosphorylatable JAM-A/S285A mutant expression; 3D cyst culture; PP2A inhibitor/identification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro direct binding, mutagenesis of phosphosite, PP2A identified as eraser, multiple functional readouts including 3D morphogenesis","pmids":["22371556"],"is_preprint":false},{"year":2012,"finding":"JAM-A in resting platelets functions as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling; Jam-A-deficient mice show augmented platelet spreading and clot retraction without changes in inside-out signaling (granule secretion, TxA2 generation, or fibrinogen receptor activation).","method":"Jam-A genetic knockout mice; in vivo thrombosis models; ex vivo platelet aggregation, spreading, and clot retraction assays; granule secretion and fibrinogen receptor activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple dissecting assays separating inside-out from outside-in signaling","pmids":["22271446"],"is_preprint":false},{"year":2013,"finding":"JAM-A associates directly with ZO-2 and indirectly with afadin; this complex together with PDZ-GEF1 activates Rap2c; loss of any component increases paracellular permeability. JAM-A also modulates RhoA activity and non-muscle myosin phosphorylation to control apical actomyosin contraction.","method":"Co-immunoprecipitation (direct ZO-2 binding, indirect afadin); siRNA knockdown of complex components; paracellular permeability assays; RhoA activity and myosin phosphorylation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying complex, siRNA epistasis, multiple pathway readouts; consistent with KO mouse data","pmids":["23885123"],"is_preprint":false},{"year":2013,"finding":"Mast cell tryptase reduces JAM-A protein expression in intestinal epithelial cells, contributing to decreased transepithelial resistance and increased permeability; tryptase inhibition with nafamostat mesilate rescues JAM-A levels and barrier function.","method":"Caco-2 monolayers treated with tryptase; Caco-2/HMC-1 co-culture with mast cell degranulation; TER and FITC-dextran flux; Western blot and immunofluorescence for JAM-A; nafamostat mesilate inhibition","journal":"The American journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue of JAM-A expression, multiple barrier readouts, single lab","pmids":["23588236"],"is_preprint":false},{"year":2014,"finding":"JAM-A functions as a coreceptor for rotavirus entry; JAM-A supports entry of strains RRV, Wa, and UK but not YM; reassortant analysis showed the viral spike protein VP4 determines use of JAM-A as coreceptor.","method":"Antibody blocking and siRNA knockdown of JAM-A in MA104 cells; rotavirus infection assays; RRV×YM reassortant virus analysis","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (siRNA KD), antibody blocking, and viral reassortant genetic epistasis; multiple orthogonal approaches","pmids":["25481868"],"is_preprint":false},{"year":2014,"finding":"JAM-A trans-dimerization (between cells) occurs at a site distinct from cis-dimerization (on same cell surface); trans-dimerization requires residues 43NNP45 and activates Rap2 signaling; cis-null but not trans-null JAM-A mutants show enhanced bead clustering; confluent cells with enabled trans-dimerization have enhanced Rap2 activity.","method":"Alanine substitution mutants (NNP-JAM-A, cis-null); microsphere aggregation assays; atomic force microscopy; Rap2 activity assays; transfection in confluent vs. sparse cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of distinct dimerization interfaces, AFM biophysics, and signaling readout; multiple orthogonal approaches, single lab","pmids":["24672055"],"is_preprint":false},{"year":2015,"finding":"JAM-A regulates planar spindle orientation in polarized epithelial cells during mitosis by triggering transient Cdc42 and PI(3)K activation, generating a cortical PtdIns(3,4,5)P3 gradient and organizing cortical F-actin; loss of JAM-A reduces dynactin localization at the cortex, misaligns the spindle, and compromises epithelial morphogenesis in 3D culture.","method":"JAM-A KO/knockdown; live-cell imaging of spindle orientation; Cdc42 and PI(3)K activity assays; dynactin localization by immunofluorescence; 3D cyst culture","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function, live imaging, signaling activity assays, and 3D morphogenesis phenotype; multiple orthogonal methods","pmids":["26306570"],"is_preprint":false},{"year":2016,"finding":"Tension applied to JAM-A activates RhoA via GEF-H1 and p115 RhoGEF; activation is PI3K-dependent and regulated by FAK/ERK and Src family kinases respectively; phosphorylation of JAM-A at Ser-284 is required for RhoA activation in response to tension.","method":"Mechanical tension applied to JAM-A via antibody-bead system; RhoA activity assays; kinase inhibitors (FAK, ERK, Src, PI3K); S284 phosphomutant expression; GEF-H1 and p115 RhoGEF siRNA","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanotransduction assay with phosphomutant and siRNA epistasis; multiple pathway dissection experiments; single lab","pmids":["26985018"],"is_preprint":false},{"year":2019,"finding":"JAM-A tyrosine at Y280 in its cytoplasmic tail is phosphorylated by Yes-1 kinase and dephosphorylated by PTPN13; cytokine exposure (TNFα, IFNγ, IL-22, IL-17A) increases p-Y280 in a Src-dependent manner; Y280 phosphorylation reduces JAM-A association with active Rap2 and impairs barrier function.","method":"Phospho-specific antibodies; siRNA knockdown of Yes-1 and PTPN13; Src inhibitor PP2; Rap2 activity assays; TER and dextran flux; colitis patient biopsies and murine colitis model","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified kinase (Yes-1) and phosphatase (PTPN13), phosphomutant correlation with signaling and barrier readouts, pharmacological rescue, validated in vivo","pmids":["30625033"],"is_preprint":false},{"year":2019,"finding":"Claudins and JAM-A coordinately regulate tight junction strand assembly and epithelial polarity; simultaneous deletion of claudins and JAM-A in epithelial cells results in loss of membrane appositions, loss of macromolecule permeability barrier, and sporadic epithelial polarity defects.","method":"Systematic genome editing knockout of TJ components (ZO-1/ZO-2, claudins, JAM-A) individually and in combination; electron microscopy; barrier assays; polarity markers","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genome-edited KO with multiple orthogonal structural and functional readouts; rigorous epistasis design","pmids":["31467165"],"is_preprint":false},{"year":2020,"finding":"JAM-A promotes C/EBP-α expression through suppression of β-catenin transcriptional activity and activation of EPAC; C/EBP-α then directly binds the claudin-5 promoter to drive claudin-5 transcription, reducing endothelial permeability; genetic deletion of JAM-A in mice decreases vascular claudin-5.","method":"JAM-A knockout mice; gain/loss-of-function for C/EBP-α; FITC-dextran permeability assays; ChIP/promoter binding of C/EBP-α at claudin-5 promoter; EPAC activation assays; patient tumor biopsies","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo, gain/loss-of-function epistasis, ChIP for transcription factor binding; multiple orthogonal methods","pmids":["32673519"],"is_preprint":false},{"year":2020,"finding":"JAM-A depletion stimulates junctional recruitment of p114RhoGEF/ARHGEF18, increases mechanical tension on ZO-1 (measured by FRET tension sensor), and increases traction forces at focal adhesions; p114RhoGEF is required for junctional actomyosin activation on stiff but not soft extracellular matrix.","method":"ZO-1-based FRET tension sensor; traction force microscopy; JAM-A siRNA depletion; p114RhoGEF knockdown; hydrogels of varying stiffness","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — FRET tension sensor (quantitative mechanobiology), siRNA epistasis, traction force microscopy; multiple orthogonal approaches","pmids":["32697990"],"is_preprint":false},{"year":2012,"finding":"CASK on the sperm flagellum acts as a common PDZ-domain-mediated interacting partner of both JAM-A and PMCA4b; CASK-JAM-A interaction promotes PMCA4b Ca2+ efflux activity, while CASK-PMCA4b interaction inhibits it; in Jam-A null sperm, increased CASK-PMCA4b interaction inhibits PMCA4b, causing Ca2+ accumulation and reduced ATP.","method":"Co-immunoprecipitation of CASK with JAM-A and PMCA4b on sperm flagellum; JAM-A KO mice; cytosolic Ca2+ measurement; ATP measurement; PMCA4b enzymatic activity","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying ternary complex, KO phenotype, enzyme activity assay; single lab","pmids":["22020416"],"is_preprint":false},{"year":2021,"finding":"ADAM17 cleaves JAM-A/F11R at the endothelial junction; aging-related increase in ADAM17 expression reduces junctional JAM-A, impairing endothelial wall shear stress mechanosensing; expression of ADAM17-cleavage-resistant JAM-AV232Y rescues impaired mechanosensing both in vitro and in aged mice in vivo.","method":"AAV9-mediated ADAM17 overexpression in resistance arteries; ADAM17 activation in cultured endothelial cells under flow; JAM-A knockdown; overexpression of cleavage-resistant JAM-AV232Y mutant; arterial remodeling measurements in aged mice","journal":"GeroScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified ADAM17 as sheddase with cleavage-resistant rescue mutant, in vivo validation; single lab","pmids":["34718985"],"is_preprint":false},{"year":2022,"finding":"JAM-A signals through the Hippo pathway to regulate intestinal epithelial proliferation: JAM-A interacts with NF2 and LATS1; JAM-A deficiency increases YAP activity; a dimerization-deficient mutant (JAM-A-DL1) phenocopies JAM-A deficiency, failing to activate Hippo; downstream, EVI1 transcription factor contributes to pro-proliferative gene expression.","method":"Co-immunoprecipitation of JAM-A with NF2 and LATS1; YAP activity assays in JAM-A-deficient IEC; overexpression of JAM-A-DL1 vs. JAM-A-WT; EVI1 functional studies","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying Hippo complex components, dimerization-null mutant epistasis, signaling readouts; single lab","pmids":["35602956"],"is_preprint":false},{"year":2022,"finding":"JAM-A exists in a complex with α3β1 integrin and tetraspanins CD151 and CD9 through its extracellular domain; this complex regulates collective cell migration on laminin and collagen-I substrates but not fibronectin or vitronectin; depletion of any component slows collective migration.","method":"Co-immunoprecipitation; domain mapping experiments; MDCK cell siRNA depletion of JAM-A, α3β1, CD151, CD9; collective cell migration assays on different ECM substrates","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, siRNA of multiple complex components, substrate-specificity experiments; single lab","pmids":["35067832"],"is_preprint":false},{"year":2022,"finding":"JAM-A is part of a multimolecular complex in which tetraspanins CD9 and CD81 link JAM-A to αvβ5 integrin; JAM-A binds Csk and inhibits αvβ5-associated Src activity; loss of JAM-A increases Erk1/2, Abi1, paxillin, and Rac1 activity at contact sites, causing cells to fail contact inhibition of locomotion.","method":"Co-immunoprecipitation; JAM-A depletion; Csk pulldown; Src, Erk1/2, Rac1 activity assays; contact inhibition of locomotion video microscopy; αvβ5 integrin engagement experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying complex, Csk binding, multiple downstream signaling readouts, live-cell CIL assay; multiple orthogonal methods","pmids":["35293964"],"is_preprint":false},{"year":2023,"finding":"A cytokine-induced ROCK2/JAM-A complex in lymphatic endothelial cells mediates junction tightening and impaired lymphatic drainage; lymphatic-specific ROCK2 knockout in mice reverses lymphedema in vivo.","method":"Microfluidic lymphatic drainage-on-chip; co-IP of ROCK2 and JAM-A; ROCK isoform characterization; ROCK inhibition; lymphatic-specific ROCK2 conditional KO mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying ROCK2/JAM-A complex, microfluidic functional model, genetic KO in vivo with disease rescue; multiple orthogonal methods","pmids":["37782785"],"is_preprint":false},{"year":2010,"finding":"F11R/JAM-A is expressed in cytokine-stimulated smooth muscle cells (but not in resting SMCs); siRNA silencing of F11R in cytokine-stimulated SMCs blocks both their proliferation and migration, identifying F11R as required for inflamed SMC behavior relevant to atherogenesis.","method":"RT-PCR and Western blot for F11R in cytokine-stimulated aortic SMCs; siRNA silencing of F11R; SMC migration and proliferation assays","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined proliferation/migration readouts; single lab, single method per endpoint","pmids":["20627246"],"is_preprint":false},{"year":2011,"finding":"De novo transcription and translation of F11R in endothelial cells, induced by pro-inflammatory cytokines via NF-κB and JAK/STAT pathways, is required for cytokine-induced insertion of F11R on the EC luminal surface and subsequent platelet adhesion; F11R-specific siRNA and NF-κB/JAK-STAT inhibitors block both F11R upregulation and platelet adhesion.","method":"mRNA synthesis inhibitors (actinomycin); NF-κB inhibitor (parthenolide); JAK/STAT inhibitor (AG-480); F11R-specific siRNA transfection; F11R mRNA and protein quantification; platelet adhesion assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitors and siRNA epistasis with functional platelet adhesion readout; single lab","pmids":["21703019"],"is_preprint":false},{"year":2007,"finding":"JAM-A is both essential for and inhibitory to hepatic polarity development in WIF-B cells; the cytoplasmic tail PDZ-binding motif and Thr273 phosphorylation site are required for polarity function; overexpression of wild-type or phosphomutant JAM-A blocks hepatic maturation, while C-terminal truncation is without effect.","method":"shRNA knockdown of JAM-A; rescue with RNA-resistant human JAM-A constructs; PDZ-binding motif deletion (huΔC-term) and phosphorylation site point mutants (T273A); hepatic polarity assays in WIF-B cells","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/rescue with domain mutants, multiple JAM-A constructs testing specific sites; single lab","pmids":["18096610"],"is_preprint":false},{"year":2004,"finding":"JAM-1 is recruited to cell-cell contacts in the mouse preimplantation embryo earlier than any other tight junction protein analyzed; at the eight-cell stage it transiently localizes to the apical microvillous pole where PKCζ and PKCδ are found; anti-JAM-1 neutralizing antibodies delayed blastocoel cavity formation without affecting compaction.","method":"Immunofluorescence confocal microscopy in staged embryos; anti-JAM-1 neutralizing antibody treatment; comparison with other TJ proteins","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with neutralizing antibody functional experiment; single lab","pmids":["15494378"],"is_preprint":false},{"year":2013,"finding":"F11R/JAM-A mRNA is stabilized and retained in the nucleus under hypoxia via ADAR1-mediated RNA editing; hyper-edited mature F11R mRNAs associate with p54nrb and accumulate in the nucleus, preventing export and translation.","method":"Hypoxia treatment; ADAR1/ADAR2 knockdown; nuclear/cytoplasmic fractionation; RNA immunoprecipitation with p54nrb; RNA editing analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ADAR1 identified as writer, p54nrb as nuclear retention factor, fractionation experiments; single lab","pmids":["24147060"],"is_preprint":false},{"year":2008,"finding":"Nectin-3, requiring its binding partner afadin, is required for co-localization of JAM-A and claudin-1 at the same cell-cell adhesion membrane domain in L fibroblasts; without nectin-3, JAM-A and claudin-1 form separate adhesion domains.","method":"Transfection of L fibroblasts with combinations of JAM-A, claudin-1, nectin-3, E-cadherin; immunofluorescence co-localization analysis; afadin requirement tested","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution in non-junctional cells with defined protein combinations; single lab","pmids":["18547333"],"is_preprint":false},{"year":2022,"finding":"HOXD11 directly binds to the JAM-A gene promoter to transcriptionally upregulate JAM-A expression; JAM-A in turn activates the NF-κB signaling pathway to promote proliferation, invasion, and migration in esophageal squamous cell carcinoma.","method":"ChIP and promoter binding assays for HOXD11 at JAM-A promoter; JAM-A knockdown; NF-κB pathway activity assays; in vitro and in vivo functional assays","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct transcription factor binding to promoter, functional downstream pathway assays; single lab","pmids":["36214988"],"is_preprint":false},{"year":2022,"finding":"JAM-A transcriptionally regulates HER2 expression by influencing the binding of transcription factor FOXA1 to a specific site in the HER2 gene promoter; this pathway is unidirectional (JAM-A → FOXA1 → HER2).","method":"Targeted disruption of JAM-A, FOXA1, HER2 individually; in silico HER2 promoter analysis; cellular expression studies; correlation in cancer databases","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression studies with targeted disruption but no direct ChIP of FOXA1 at HER2 promoter explicitly reported in abstract; single lab","pmids":["35203384"],"is_preprint":false}],"current_model":"F11R/JAM-A is a multifunctional immunoglobulin superfamily transmembrane protein at tight junctions of endothelial and epithelial cells and on platelets/leukocytes, where it (1) mediates homophilic trans-dimerization and heterophilic LFA-1 engagement to control leukocyte transendothelial migration; (2) regulates barrier function through a ZO-2/afadin/PDZ-GEF1/Rap2c signaling axis and a JAM-A→EPAC→C/EBP-α→claudin-5 transcriptional pathway, with barrier disruption driven by Yes-1-mediated Y280 phosphorylation and antagonized by PTPN13; (3) acts as a mechanosensor — tension on JAM-A activates RhoA via GEF-H1/p115 RhoGEF (Ser284-dependent), and ROCK2 forms a complex with JAM-A to regulate lymphatic junction tension; (4) controls epithelial polarity and spindle orientation by activating Cdc42/PI(3)K to localize dynactin cortically; (5) inhibits integrin αIIbβ3 outside-in signaling in platelets while being processed by ADAM17 in aging endothelium; and (6) initiates Hippo signaling (via NF2/LATS1) to suppress intestinal epithelial proliferation and participates in a CD9/CD81/αvβ5 integrin complex to enforce contact inhibition of locomotion."},"narrative":{"mechanistic_narrative":"F11R/JAM-A is an immunoglobulin-superfamily transmembrane adhesion receptor of endothelial and epithelial junctions, platelets, and leukocytes that converts adhesive engagement into intracellular signaling to control leukocyte trafficking, junctional barrier function, epithelial polarity, and cell proliferation [PMID:11812992, PMID:18039951, PMID:23885123]. Through its extracellular Ig domains it engages two adhesive modes: a homophilic trans-interaction stabilized by the second Ig domain and a stronger heterophilic interaction with the β2 integrin LFA-1, whose binding to domain 2 cancels homophilic stabilization and drives leukocyte adhesion and transendothelial migration [PMID:11812992, PMID:18849408]; trans-dimerization requires residues 43NNP45 and activates Rap2 signaling [PMID:24672055]. In inflamed endothelium JAM-A is transcriptionally induced via NF-κB and JAK/STAT and inserted on the luminal surface to support platelet adhesion, and acts sequentially with ICAM-2 and PECAM-1 to mediate stimulus-specific leukocyte transmigration [PMID:21703019, PMID:19211506, PMID:17505016]. At junctions JAM-A nucleates a ZO-2/afadin/PDZ-GEF1 complex that activates Rap2c and tunes RhoA-dependent actomyosin contraction to restrict paracellular permeability [PMID:23885123], and drives a C/EBP-α-dependent transcriptional program that upregulates claudin-5 to tighten endothelial barriers [PMID:32673519]. Barrier control is gated by phosphorylation: aPKC phosphorylates Ser285 to promote junction maturation and single-lumen specification (reversed by PP2A) [PMID:22371556], while Yes-1-mediated Y280 phosphorylation, opposed by PTPN13, uncouples JAM-A from active Rap2 and disrupts the barrier during cytokine exposure [PMID:30625033]. JAM-A also functions as a mechanosensor, with tension activating RhoA through GEF-H1 and p115 RhoGEF in a Ser284-dependent manner, and its loss redistributing tension to a p114RhoGEF/ZO-1 axis [PMID:26985018, PMID:32697990]. In epithelia it restrains proliferation in a dimerization-dependent manner by inhibiting Akt/β-catenin signaling and by engaging the Hippo pathway through NF2 and LATS1 to suppress YAP activity [PMID:21372850, PMID:35602956], and it orients the mitotic spindle by triggering Cdc42/PI(3)K signaling to localize cortical dynactin [PMID:26306570]. In platelets JAM-A acts as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling [PMID:22271446], and at cell contacts it assembles with tetraspanins CD9/CD81 and αvβ5 integrin, binding Csk to suppress Src and enforce contact inhibition of locomotion [PMID:35293964]. JAM-A additionally serves as a strain-specific rotavirus coreceptor whose use is determined by viral VP4 [PMID:25481868].","teleology":[{"year":2002,"claim":"Established JAM-A as an adhesive receptor with defined ligands, resolving how a junctional Ig-superfamily protein mediates both leukocyte trafficking and platelet adhesion.","evidence":"JAM-1 transfection with LFA-1-dependent adhesion/transmigration assays and domain deletion; platelet adhesion to inflamed endothelium blocked by soluble F11R and domain peptides","pmids":["11812992","12428104","12008956"],"confidence":"High","gaps":["Atomic-resolution structure of the LFA-1 binding interface not defined here","Relative in vivo contribution of homophilic vs heterophilic engagement unresolved"]},{"year":2003,"claim":"Showed JAM-A engages integrin partners and signals via its cytoplasmic domain, linking adhesion to MAP kinase and angiogenic responses.","evidence":"Co-IP of JAM-1/αvβ3, cytoplasmic domain mutagenesis, and endothelial tube formation assays","pmids":["12750158"],"confidence":"High","gaps":["Direct vs indirect nature of αvβ3 association not defined","Cytoplasmic effectors linking JAM-A to MAPK not identified in this study"]},{"year":2007,"claim":"Defined the in vivo physiological roles of JAM-A in leukocyte transmigration and intestinal barrier function using genetic loss-of-function.","evidence":"Intravital microscopy and barrier assays in JAM-A knockout mice plus antibody blockade and siRNA, with PECAM-1 epistasis and claudin expression analysis","pmids":["17505016","18039951"],"confidence":"High","gaps":["Mechanism coupling endothelial JAM-A to transmigration step not molecularly resolved","How JAM-A loss raises claudin-10/-15 expression not established"]},{"year":2009,"claim":"Quantified the competition between homophilic and heterophilic adhesion and revealed JAM-A's cell-autonomous role in integrin recycling during chemotaxis.","evidence":"Atomic force microscopy adhesion measurements with domain mutants; JAM-A-null neutrophil chemotaxis with β1-integrin co-clustering and internalization assays; triple-KO intravital epistasis","pmids":["18849408","19118219","19211506"],"confidence":"High","gaps":["Adaptor linking JAM-A to β1-integrin endosomal trafficking not identified","Hierarchy of ICAM-2/JAM-A/PECAM-1 across stimuli not fully mapped"]},{"year":2012,"claim":"Identified the phospho-regulatory code of the cytoplasmic tail, with aPKC/PP2A acting on Ser285 to control junction maturation and lumen specification.","evidence":"Direct aPKC-JAM-A binding, S285A phosphomutant, PP2A identification, and 3D cyst morphogenesis assays","pmids":["22371556"],"confidence":"High","gaps":["Downstream effectors of Ser285 phosphorylation not fully defined","Interplay with other tail phosphosites not addressed here"]},{"year":2011,"claim":"Established JAM-A as a dimerization-dependent brake on epithelial proliferation via Akt/β-catenin inhibition, connecting adhesion to growth control.","evidence":"JAM-A KO mice with β-catenin/TCF reporter, Akt inhibitor rescue, and dimerization-deficient mutant expression","pmids":["21372850"],"confidence":"High","gaps":["Direct molecular link from JAM-A dimerization to Akt not defined","Cell-type generality of the proliferation control untested"]},{"year":2013,"claim":"Resolved the junctional signaling complex through which JAM-A activates Rap2c and tunes actomyosin contraction to set paracellular permeability.","evidence":"Co-IP defining direct ZO-2 and indirect afadin binding, PDZ-GEF1/Rap2c activation, siRNA epistasis, and RhoA/myosin assays","pmids":["23885123"],"confidence":"High","gaps":["Stoichiometry and dynamics of the ZO-2/afadin/PDZ-GEF1 complex not defined","How Rap2c output feeds back on RhoA not detailed"]},{"year":2014,"claim":"Separated cis- from trans-dimerization interfaces and showed trans-dimerization is the signaling-competent mode coupling cell confluence to Rap2 activity; identified JAM-A as a strain-specific rotavirus coreceptor.","evidence":"Distinct-interface alanine mutants with AFM and Rap2 assays; antibody/siRNA blocking with VP4 reassortant virus analysis","pmids":["24672055","25481868"],"confidence":"High","gaps":["Structural basis of NNP-mediated trans-dimerization not solved","VP4 region contacting JAM-A not mapped"]},{"year":2015,"claim":"Defined JAM-A's role in mitotic spindle orientation, extending its function from junction maintenance to oriented epithelial morphogenesis.","evidence":"JAM-A loss-of-function with live spindle imaging, Cdc42/PI(3)K activity assays, dynactin localization, and 3D cyst culture","pmids":["26306570"],"confidence":"High","gaps":["How JAM-A triggers transient Cdc42 activation at the cortex not resolved","Link between PtdIns(3,4,5)P3 gradient and dynactin recruitment not detailed"]},{"year":2016,"claim":"Established JAM-A as a tension-sensing receptor that activates RhoA through GEF-H1/p115 RhoGEF in a Ser284-dependent manner.","evidence":"Antibody-bead tension application, RhoA assays, kinase inhibitors, S284 phosphomutant, and GEF siRNA","pmids":["26985018"],"confidence":"High","gaps":["Force-sensing structural element of JAM-A not identified","Relationship between Ser284 (tension) and Ser285 (aPKC) phosphorylation not reconciled"]},{"year":2019,"claim":"Completed the tyrosine phospho-switch for barrier control by identifying Yes-1 and PTPN13 as the Y280 kinase/phosphatase pair that gates JAM-A–Rap2 coupling under inflammation, and placed JAM-A within tight-junction strand assembly genetically.","evidence":"Phospho-specific antibodies, Yes-1/PTPN13 siRNA, Src inhibitor, Rap2 assays, colitis models; systematic genome-edited combinatorial KO of TJ components with EM","pmids":["30625033","31467165"],"confidence":"High","gaps":["Crosstalk between Y280 and Ser285/Ser284 phosphorylation events not integrated","Direct structural role of JAM-A in strand assembly versus claudins not separated"]},{"year":2020,"claim":"Defined the transcriptional and mechanical outputs of JAM-A barrier control: a C/EBP-α→claudin-5 program and a p114RhoGEF/ZO-1 tension axis engaged upon JAM-A loss.","evidence":"JAM-A KO mice with C/EBP-α gain/loss and ChIP at the claudin-5 promoter; ZO-1 FRET tension sensor and traction force microscopy with p114RhoGEF knockdown on variable-stiffness substrates","pmids":["32673519","32697990"],"confidence":"High","gaps":["How JAM-A activates EPAC upstream of C/EBP-α not mechanistically detailed","Trigger that recruits p114RhoGEF upon JAM-A depletion not identified"]},{"year":2022,"claim":"Connected JAM-A to the Hippo pathway and to tetraspanin/integrin complexes that enforce contact inhibition and direct collective migration.","evidence":"Co-IP of JAM-A with NF2/LATS1 and dimerization-null mutant epistasis with YAP readout; co-IP/domain mapping of CD9/CD81/αvβ5 and α3β1/CD151/CD9 complexes with Csk pulldown, Src/Rac1 assays, and CIL/migration assays","pmids":["35602956","35293964","35067832"],"confidence":"High","gaps":["Direct vs scaffolded nature of JAM-A–NF2/LATS1 interaction not resolved","How tetraspanin complexes are spatially coordinated with junctional JAM-A pools unclear"]},{"year":2023,"claim":"Showed a cytokine-induced ROCK2/JAM-A complex tightens lymphatic junctions and impairs drainage, with genetic ROCK2 deletion reversing lymphedema.","evidence":"Microfluidic lymphatic drainage-on-chip, ROCK2/JAM-A co-IP, ROCK inhibition, and lymphatic-specific ROCK2 conditional KO mice","pmids":["37782785"],"confidence":"High","gaps":["Structural basis of the ROCK2/JAM-A interaction not defined","How this complex relates to the GEF-H1/p115 tension pathway not integrated"]},{"year":null,"claim":"How the multiple JAM-A cytoplasmic phosphorylation events (Ser284, Ser285, Y280, Thr273) and competing GEF/integrin/tetraspanin partners are integrated into a single context-dependent output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling distinct phosphosites to barrier, mechanics, and proliferation outputs","Structural details of trans-dimer and partner complexes largely undefined","Tissue-specific selection among competing effector pathways not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,9,17]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,19,23,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,28]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14,26,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,7,31]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,19,22,26]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,13,31]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[14,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,18,33]}],"complexes":["JAM-A/ZO-2/afadin/PDZ-GEF1 junctional complex","JAM-A/CD9/CD81/αvβ5 integrin complex","JAM-A/α3β1/CD151/CD9 complex","JAM-A/CASK/PMCA4b sperm flagellar complex"],"partners":["ITGAL","ZO-2","AFADIN","ITGAV","CD9","PTPN13","NF2","ROCK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y624","full_name":"Junctional adhesion molecule A","aliases":["Junctional adhesion molecule 1","JAM-1","Platelet F11 receptor","Platelet adhesion molecule 1","PAM-1"],"length_aa":299,"mass_kda":32.6,"function":"Seems to play a role in epithelial tight junction formation. Appears early in primordial forms of cell junctions and recruits PARD3 (PubMed:11489913). The association of the PARD6-PARD3 complex may prevent the interaction of PARD3 with JAM1, thereby preventing tight junction assembly (By similarity). Plays a role in regulating monocyte transmigration involved in integrity of epithelial barrier (By similarity). Ligand for integrin alpha-L/beta-2 involved in memory T-cell and neutrophil transmigration (PubMed:11812992). Involved in platelet activation (PubMed:10753840) (Microbial infection) Acts as a receptor for Mammalian reovirus sigma-1 (Microbial infection) Acts as a receptor for Human Rotavirus strain Wa","subcellular_location":"Cell junction, tight junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y624/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/F11R","classification":"Not Classified","n_dependent_lines":61,"n_total_lines":1208,"dependency_fraction":0.050496688741721855},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/F11R","total_profiled":1310},"omim":[{"mim_id":"605721","title":"JUNCTION ADHESION MOLECULE 1; JAM1","url":"https://www.omim.org/entry/605721"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Microtubules","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/F11R"},"hgnc":{"alias_symbol":["PAM-1","JCAM","JAM-1","JAM-A","JAMA","CD321"],"prev_symbol":["JAM1"]},"alphafold":{"accession":"Q9Y624","domains":[{"cath_id":"2.60.40.10","chopping":"28-128","consensus_level":"high","plddt":96.6441,"start":28,"end":128},{"cath_id":"2.60.40.10","chopping":"135-231","consensus_level":"high","plddt":96.4337,"start":135,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y624","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y624-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y624-F1-predicted_aligned_error_v6.png","plddt_mean":87.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=F11R","jax_strain_url":"https://www.jax.org/strain/search?query=F11R"},"sequence":{"accession":"Q9Y624","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y624.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y624/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y624"}},"corpus_meta":[{"pmid":"11812992","id":"PMC_11812992","title":"JAM-1 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experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays with domain mutants, replicated across T cells and neutrophils in multiple conditions\",\n      \"pmids\": [\"11812992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"F11R/JAM-A mediates platelet adhesion to cytokine-inflamed endothelial cells through homophilic interactions; peptides spanning the N-terminal region and first Ig-fold of F11R inhibit this adhesion, identifying those regions as the adhesive interface.\",\n      \"method\": \"Platelet adhesion assays to immobilized recombinant sF11R and to cytokine-stimulated HUVEC; inhibition by recombinant sF11R and domain-specific peptides\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal inhibition approaches (soluble protein, peptides), replicated across platelet-endothelial cell adhesion assays\",\n      \"pmids\": [\"12428104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Two regions of F11R — the N-terminal sequence (S1–C23) and the K70–C82 sequence in the first Ig-fold — are critical for M.Ab.F11-induced platelet aggregation, adhesion, and potentiation; a soluble recombinant sF11R completely inhibits these responses.\",\n      \"method\": \"Peptide inhibition studies of M.Ab.F11-mediated platelet aggregation, adhesion, and potentiation; 3D structure modeling of the extracellular domain\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide inhibition assays with domain mapping, single lab, multiple functional readouts\",\n      \"pmids\": [\"12008956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JAM-1/A and integrin αvβ3 form a complex in quiescent endothelial cells; bFGF treatment causes JAM-1 to redistribute to the cell surface and dissociates the JAM-1/αvβ3 complex, enabling MAP kinase activation required for bFGF-induced angiogenesis. Mutation of the JAM-1 cytoplasmic domain blocks bFGF-induced MAP kinase activation and tube formation.\",\n      \"method\": \"Co-immunoprecipitation; cytoplasmic domain mutagenesis; endothelial cell morphology, proliferation, and tube formation assays; antibody blockade\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP identifying complex, cytoplasmic domain mutagenesis with defined phenotypic readouts, multiple orthogonal assays in a single study\",\n      \"pmids\": [\"12750158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"F11R/JAM-A in platelets signals through phosphoinositide-3-kinase activation; M.Ab.F11 crosslinking of F11R with FcγRII induces actin filament assembly, phosphorylation of the 32 and 35 kDa F11R forms, F11R dimerization, and association of F11R with integrin GPIIIa and CD9.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assays; wortmannin inhibition; platelet aggregation and spreading assays\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating complex with GPIIIa/CD9, phosphorylation assays, PI3K inhibitor experiments; single lab\",\n      \"pmids\": [\"15344881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A deficiency in vivo (knockout mice and neutralizing antibody) specifically reduces leukocyte transmigration (but not adhesion) in response to IL-1β or ischemia/reperfusion stimuli, but not to LTB4 or PAF; endothelial-cell JAM-A is the relevant pool; JAM-A and PECAM-1 act sequentially in this transmigration process.\",\n      \"method\": \"Intravital microscopy in JAM-A KO mice and antibody-treated mice; leukocyte transfer experiments; dual blockade/deletion epistasis analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus antibody blockade, leukocyte transfer epistasis, replicated across multiple inflammatory stimuli\",\n      \"pmids\": [\"17505016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A deficiency increases intestinal epithelial permeability in vivo and in vitro, associated with increased expression of claudin-10 and claudin-15 in colonic mucosa and JAM-A siRNA-treated cells.\",\n      \"method\": \"JAM-A knockout mice; dextran flux and transepithelial resistance assays; siRNA knockdown in epithelial cells; Western blot for claudin isoforms\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus siRNA in matched in vitro/in vivo model with multiple barrier readouts\",\n      \"pmids\": [\"18039951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A is present on the plasma membrane of sperm flagella; deletion of Jam-A causes flagellar ultrastructural defects and significantly impairs progressive and hyperactivated sperm motility before and after capacitation.\",\n      \"method\": \"Immunolocalization; gene-trap JAM-A knockout mice; sperm motility analysis; electron microscopy of flagellar ultrastructure\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined ultrastructural and motility phenotype, direct localization by immunofluorescence; single lab\",\n      \"pmids\": [\"18022613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JAM-A on neutrophils is required cell-autonomously for chemotaxis: it concentrates at the leading edge and uropod, is internalized with β1 integrin into endosomal vesicles, and is required for correct internalization and recycling of β1 integrins during migration; clustering of β1 integrin co-clusters JAM-A but not vice versa.\",\n      \"method\": \"JAM-A null neutrophil chemotaxis assays in vivo and in vitro; co-clustering experiments; BAPTA-AM inhibition of integrin internalization; intravital microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null phenotype combined with pharmacological rescue and co-clustering experiments; multiple orthogonal methods\",\n      \"pmids\": [\"19118219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LFA-1 binding to domain 2 of JAM-A destabilizes the JAM-A homophilic interaction; the second Ig domain of JAM-A stabilizes the homophilic interaction, and LFA-1 binding to this domain cancels this stabilization; the LFA-1/JAM-A heterophilic interaction is stronger than the JAM-A homophilic interaction.\",\n      \"method\": \"Competitive binding assays; atomic force microscopy adhesion measurements with domain deletion mutants and LFA-1 inserted domain\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative biophysical (AFM) plus domain deletion mutants; single lab but rigorous mechanistic characterization\",\n      \"pmids\": [\"18849408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ICAM-2, JAM-A, and PECAM-1 act sequentially to mediate neutrophil transendothelial migration in a stimulus-dependent manner; when direct neutrophil stimulation is blocked, TNF-α-induced transmigration becomes dependent on all three endothelial molecules.\",\n      \"method\": \"Cell-transfer technique with TNFR-deficient leukocytes; fluorescence intravital microscopy in ICAM-2-/-, JAM-A-/-, PECAM-1-/- mice; analysis of arrest sites\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic triple-KO epistasis, intravital microscopy, cell-transfer approach demonstrating sequential action\",\n      \"pmids\": [\"19211506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAM-A restricts intestinal epithelial cell proliferation in a dimerization-dependent manner by inhibiting Akt-dependent β-catenin activation; JAM-A-deficient IECs show enhanced β-catenin-dependent transcription, and Akt inhibition reverses colonic crypt hyperproliferation in JAM-A KO mice.\",\n      \"method\": \"JAM-A KO mice; transgenic β-catenin/TCF reporter mice; Akt inhibitor treatment; in vitro dimerization-deficient mutant expression\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary in vivo and in vitro epistasis with pharmacological and genetic rescue\",\n      \"pmids\": [\"21372850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"aPKC directly interacts with JAM-A independent of PAR-3 and phosphorylates JAM-A at Ser285; this phosphorylation is required for maturation of cell-cell contacts, tight junction formation, and single lumen specification. Protein phosphatase 2A dephosphorylates JAM-A at Ser285, antagonizing aPKC.\",\n      \"method\": \"Direct binding assays (aPKC–JAM-A); phospho-specific antibodies; non-phosphorylatable JAM-A/S285A mutant expression; 3D cyst culture; PP2A inhibitor/identification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro direct binding, mutagenesis of phosphosite, PP2A identified as eraser, multiple functional readouts including 3D morphogenesis\",\n      \"pmids\": [\"22371556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JAM-A in resting platelets functions as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling; Jam-A-deficient mice show augmented platelet spreading and clot retraction without changes in inside-out signaling (granule secretion, TxA2 generation, or fibrinogen receptor activation).\",\n      \"method\": \"Jam-A genetic knockout mice; in vivo thrombosis models; ex vivo platelet aggregation, spreading, and clot retraction assays; granule secretion and fibrinogen receptor activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple dissecting assays separating inside-out from outside-in signaling\",\n      \"pmids\": [\"22271446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JAM-A associates directly with ZO-2 and indirectly with afadin; this complex together with PDZ-GEF1 activates Rap2c; loss of any component increases paracellular permeability. JAM-A also modulates RhoA activity and non-muscle myosin phosphorylation to control apical actomyosin contraction.\",\n      \"method\": \"Co-immunoprecipitation (direct ZO-2 binding, indirect afadin); siRNA knockdown of complex components; paracellular permeability assays; RhoA activity and myosin phosphorylation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying complex, siRNA epistasis, multiple pathway readouts; consistent with KO mouse data\",\n      \"pmids\": [\"23885123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mast cell tryptase reduces JAM-A protein expression in intestinal epithelial cells, contributing to decreased transepithelial resistance and increased permeability; tryptase inhibition with nafamostat mesilate rescues JAM-A levels and barrier function.\",\n      \"method\": \"Caco-2 monolayers treated with tryptase; Caco-2/HMC-1 co-culture with mast cell degranulation; TER and FITC-dextran flux; Western blot and immunofluorescence for JAM-A; nafamostat mesilate inhibition\",\n      \"journal\": \"The American journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue of JAM-A expression, multiple barrier readouts, single lab\",\n      \"pmids\": [\"23588236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAM-A functions as a coreceptor for rotavirus entry; JAM-A supports entry of strains RRV, Wa, and UK but not YM; reassortant analysis showed the viral spike protein VP4 determines use of JAM-A as coreceptor.\",\n      \"method\": \"Antibody blocking and siRNA knockdown of JAM-A in MA104 cells; rotavirus infection assays; RRV×YM reassortant virus analysis\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (siRNA KD), antibody blocking, and viral reassortant genetic epistasis; multiple orthogonal approaches\",\n      \"pmids\": [\"25481868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAM-A trans-dimerization (between cells) occurs at a site distinct from cis-dimerization (on same cell surface); trans-dimerization requires residues 43NNP45 and activates Rap2 signaling; cis-null but not trans-null JAM-A mutants show enhanced bead clustering; confluent cells with enabled trans-dimerization have enhanced Rap2 activity.\",\n      \"method\": \"Alanine substitution mutants (NNP-JAM-A, cis-null); microsphere aggregation assays; atomic force microscopy; Rap2 activity assays; transfection in confluent vs. sparse cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of distinct dimerization interfaces, AFM biophysics, and signaling readout; multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"24672055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAM-A regulates planar spindle orientation in polarized epithelial cells during mitosis by triggering transient Cdc42 and PI(3)K activation, generating a cortical PtdIns(3,4,5)P3 gradient and organizing cortical F-actin; loss of JAM-A reduces dynactin localization at the cortex, misaligns the spindle, and compromises epithelial morphogenesis in 3D culture.\",\n      \"method\": \"JAM-A KO/knockdown; live-cell imaging of spindle orientation; Cdc42 and PI(3)K activity assays; dynactin localization by immunofluorescence; 3D cyst culture\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function, live imaging, signaling activity assays, and 3D morphogenesis phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"26306570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tension applied to JAM-A activates RhoA via GEF-H1 and p115 RhoGEF; activation is PI3K-dependent and regulated by FAK/ERK and Src family kinases respectively; phosphorylation of JAM-A at Ser-284 is required for RhoA activation in response to tension.\",\n      \"method\": \"Mechanical tension applied to JAM-A via antibody-bead system; RhoA activity assays; kinase inhibitors (FAK, ERK, Src, PI3K); S284 phosphomutant expression; GEF-H1 and p115 RhoGEF siRNA\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanotransduction assay with phosphomutant and siRNA epistasis; multiple pathway dissection experiments; single lab\",\n      \"pmids\": [\"26985018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAM-A tyrosine at Y280 in its cytoplasmic tail is phosphorylated by Yes-1 kinase and dephosphorylated by PTPN13; cytokine exposure (TNFα, IFNγ, IL-22, IL-17A) increases p-Y280 in a Src-dependent manner; Y280 phosphorylation reduces JAM-A association with active Rap2 and impairs barrier function.\",\n      \"method\": \"Phospho-specific antibodies; siRNA knockdown of Yes-1 and PTPN13; Src inhibitor PP2; Rap2 activity assays; TER and dextran flux; colitis patient biopsies and murine colitis model\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified kinase (Yes-1) and phosphatase (PTPN13), phosphomutant correlation with signaling and barrier readouts, pharmacological rescue, validated in vivo\",\n      \"pmids\": [\"30625033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Claudins and JAM-A coordinately regulate tight junction strand assembly and epithelial polarity; simultaneous deletion of claudins and JAM-A in epithelial cells results in loss of membrane appositions, loss of macromolecule permeability barrier, and sporadic epithelial polarity defects.\",\n      \"method\": \"Systematic genome editing knockout of TJ components (ZO-1/ZO-2, claudins, JAM-A) individually and in combination; electron microscopy; barrier assays; polarity markers\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genome-edited KO with multiple orthogonal structural and functional readouts; rigorous epistasis design\",\n      \"pmids\": [\"31467165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAM-A promotes C/EBP-α expression through suppression of β-catenin transcriptional activity and activation of EPAC; C/EBP-α then directly binds the claudin-5 promoter to drive claudin-5 transcription, reducing endothelial permeability; genetic deletion of JAM-A in mice decreases vascular claudin-5.\",\n      \"method\": \"JAM-A knockout mice; gain/loss-of-function for C/EBP-α; FITC-dextran permeability assays; ChIP/promoter binding of C/EBP-α at claudin-5 promoter; EPAC activation assays; patient tumor biopsies\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo, gain/loss-of-function epistasis, ChIP for transcription factor binding; multiple orthogonal methods\",\n      \"pmids\": [\"32673519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAM-A depletion stimulates junctional recruitment of p114RhoGEF/ARHGEF18, increases mechanical tension on ZO-1 (measured by FRET tension sensor), and increases traction forces at focal adhesions; p114RhoGEF is required for junctional actomyosin activation on stiff but not soft extracellular matrix.\",\n      \"method\": \"ZO-1-based FRET tension sensor; traction force microscopy; JAM-A siRNA depletion; p114RhoGEF knockdown; hydrogels of varying stiffness\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — FRET tension sensor (quantitative mechanobiology), siRNA epistasis, traction force microscopy; multiple orthogonal approaches\",\n      \"pmids\": [\"32697990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CASK on the sperm flagellum acts as a common PDZ-domain-mediated interacting partner of both JAM-A and PMCA4b; CASK-JAM-A interaction promotes PMCA4b Ca2+ efflux activity, while CASK-PMCA4b interaction inhibits it; in Jam-A null sperm, increased CASK-PMCA4b interaction inhibits PMCA4b, causing Ca2+ accumulation and reduced ATP.\",\n      \"method\": \"Co-immunoprecipitation of CASK with JAM-A and PMCA4b on sperm flagellum; JAM-A KO mice; cytosolic Ca2+ measurement; ATP measurement; PMCA4b enzymatic activity\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying ternary complex, KO phenotype, enzyme activity assay; single lab\",\n      \"pmids\": [\"22020416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 cleaves JAM-A/F11R at the endothelial junction; aging-related increase in ADAM17 expression reduces junctional JAM-A, impairing endothelial wall shear stress mechanosensing; expression of ADAM17-cleavage-resistant JAM-AV232Y rescues impaired mechanosensing both in vitro and in aged mice in vivo.\",\n      \"method\": \"AAV9-mediated ADAM17 overexpression in resistance arteries; ADAM17 activation in cultured endothelial cells under flow; JAM-A knockdown; overexpression of cleavage-resistant JAM-AV232Y mutant; arterial remodeling measurements in aged mice\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified ADAM17 as sheddase with cleavage-resistant rescue mutant, in vivo validation; single lab\",\n      \"pmids\": [\"34718985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A signals through the Hippo pathway to regulate intestinal epithelial proliferation: JAM-A interacts with NF2 and LATS1; JAM-A deficiency increases YAP activity; a dimerization-deficient mutant (JAM-A-DL1) phenocopies JAM-A deficiency, failing to activate Hippo; downstream, EVI1 transcription factor contributes to pro-proliferative gene expression.\",\n      \"method\": \"Co-immunoprecipitation of JAM-A with NF2 and LATS1; YAP activity assays in JAM-A-deficient IEC; overexpression of JAM-A-DL1 vs. JAM-A-WT; EVI1 functional studies\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying Hippo complex components, dimerization-null mutant epistasis, signaling readouts; single lab\",\n      \"pmids\": [\"35602956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A exists in a complex with α3β1 integrin and tetraspanins CD151 and CD9 through its extracellular domain; this complex regulates collective cell migration on laminin and collagen-I substrates but not fibronectin or vitronectin; depletion of any component slows collective migration.\",\n      \"method\": \"Co-immunoprecipitation; domain mapping experiments; MDCK cell siRNA depletion of JAM-A, α3β1, CD151, CD9; collective cell migration assays on different ECM substrates\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, siRNA of multiple complex components, substrate-specificity experiments; single lab\",\n      \"pmids\": [\"35067832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A is part of a multimolecular complex in which tetraspanins CD9 and CD81 link JAM-A to αvβ5 integrin; JAM-A binds Csk and inhibits αvβ5-associated Src activity; loss of JAM-A increases Erk1/2, Abi1, paxillin, and Rac1 activity at contact sites, causing cells to fail contact inhibition of locomotion.\",\n      \"method\": \"Co-immunoprecipitation; JAM-A depletion; Csk pulldown; Src, Erk1/2, Rac1 activity assays; contact inhibition of locomotion video microscopy; αvβ5 integrin engagement experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying complex, Csk binding, multiple downstream signaling readouts, live-cell CIL assay; multiple orthogonal methods\",\n      \"pmids\": [\"35293964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A cytokine-induced ROCK2/JAM-A complex in lymphatic endothelial cells mediates junction tightening and impaired lymphatic drainage; lymphatic-specific ROCK2 knockout in mice reverses lymphedema in vivo.\",\n      \"method\": \"Microfluidic lymphatic drainage-on-chip; co-IP of ROCK2 and JAM-A; ROCK isoform characterization; ROCK inhibition; lymphatic-specific ROCK2 conditional KO mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying ROCK2/JAM-A complex, microfluidic functional model, genetic KO in vivo with disease rescue; multiple orthogonal methods\",\n      \"pmids\": [\"37782785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"F11R/JAM-A is expressed in cytokine-stimulated smooth muscle cells (but not in resting SMCs); siRNA silencing of F11R in cytokine-stimulated SMCs blocks both their proliferation and migration, identifying F11R as required for inflamed SMC behavior relevant to atherogenesis.\",\n      \"method\": \"RT-PCR and Western blot for F11R in cytokine-stimulated aortic SMCs; siRNA silencing of F11R; SMC migration and proliferation assays\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined proliferation/migration readouts; single lab, single method per endpoint\",\n      \"pmids\": [\"20627246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"De novo transcription and translation of F11R in endothelial cells, induced by pro-inflammatory cytokines via NF-κB and JAK/STAT pathways, is required for cytokine-induced insertion of F11R on the EC luminal surface and subsequent platelet adhesion; F11R-specific siRNA and NF-κB/JAK-STAT inhibitors block both F11R upregulation and platelet adhesion.\",\n      \"method\": \"mRNA synthesis inhibitors (actinomycin); NF-κB inhibitor (parthenolide); JAK/STAT inhibitor (AG-480); F11R-specific siRNA transfection; F11R mRNA and protein quantification; platelet adhesion assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitors and siRNA epistasis with functional platelet adhesion readout; single lab\",\n      \"pmids\": [\"21703019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A is both essential for and inhibitory to hepatic polarity development in WIF-B cells; the cytoplasmic tail PDZ-binding motif and Thr273 phosphorylation site are required for polarity function; overexpression of wild-type or phosphomutant JAM-A blocks hepatic maturation, while C-terminal truncation is without effect.\",\n      \"method\": \"shRNA knockdown of JAM-A; rescue with RNA-resistant human JAM-A constructs; PDZ-binding motif deletion (huΔC-term) and phosphorylation site point mutants (T273A); hepatic polarity assays in WIF-B cells\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/rescue with domain mutants, multiple JAM-A constructs testing specific sites; single lab\",\n      \"pmids\": [\"18096610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAM-1 is recruited to cell-cell contacts in the mouse preimplantation embryo earlier than any other tight junction protein analyzed; at the eight-cell stage it transiently localizes to the apical microvillous pole where PKCζ and PKCδ are found; anti-JAM-1 neutralizing antibodies delayed blastocoel cavity formation without affecting compaction.\",\n      \"method\": \"Immunofluorescence confocal microscopy in staged embryos; anti-JAM-1 neutralizing antibody treatment; comparison with other TJ proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with neutralizing antibody functional experiment; single lab\",\n      \"pmids\": [\"15494378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"F11R/JAM-A mRNA is stabilized and retained in the nucleus under hypoxia via ADAR1-mediated RNA editing; hyper-edited mature F11R mRNAs associate with p54nrb and accumulate in the nucleus, preventing export and translation.\",\n      \"method\": \"Hypoxia treatment; ADAR1/ADAR2 knockdown; nuclear/cytoplasmic fractionation; RNA immunoprecipitation with p54nrb; RNA editing analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ADAR1 identified as writer, p54nrb as nuclear retention factor, fractionation experiments; single lab\",\n      \"pmids\": [\"24147060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nectin-3, requiring its binding partner afadin, is required for co-localization of JAM-A and claudin-1 at the same cell-cell adhesion membrane domain in L fibroblasts; without nectin-3, JAM-A and claudin-1 form separate adhesion domains.\",\n      \"method\": \"Transfection of L fibroblasts with combinations of JAM-A, claudin-1, nectin-3, E-cadherin; immunofluorescence co-localization analysis; afadin requirement tested\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution in non-junctional cells with defined protein combinations; single lab\",\n      \"pmids\": [\"18547333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXD11 directly binds to the JAM-A gene promoter to transcriptionally upregulate JAM-A expression; JAM-A in turn activates the NF-κB signaling pathway to promote proliferation, invasion, and migration in esophageal squamous cell carcinoma.\",\n      \"method\": \"ChIP and promoter binding assays for HOXD11 at JAM-A promoter; JAM-A knockdown; NF-κB pathway activity assays; in vitro and in vivo functional assays\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct transcription factor binding to promoter, functional downstream pathway assays; single lab\",\n      \"pmids\": [\"36214988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A transcriptionally regulates HER2 expression by influencing the binding of transcription factor FOXA1 to a specific site in the HER2 gene promoter; this pathway is unidirectional (JAM-A → FOXA1 → HER2).\",\n      \"method\": \"Targeted disruption of JAM-A, FOXA1, HER2 individually; in silico HER2 promoter analysis; cellular expression studies; correlation in cancer databases\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression studies with targeted disruption but no direct ChIP of FOXA1 at HER2 promoter explicitly reported in abstract; single lab\",\n      \"pmids\": [\"35203384\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"F11R/JAM-A is a multifunctional immunoglobulin superfamily transmembrane protein at tight junctions of endothelial and epithelial cells and on platelets/leukocytes, where it (1) mediates homophilic trans-dimerization and heterophilic LFA-1 engagement to control leukocyte transendothelial migration; (2) regulates barrier function through a ZO-2/afadin/PDZ-GEF1/Rap2c signaling axis and a JAM-A→EPAC→C/EBP-α→claudin-5 transcriptional pathway, with barrier disruption driven by Yes-1-mediated Y280 phosphorylation and antagonized by PTPN13; (3) acts as a mechanosensor — tension on JAM-A activates RhoA via GEF-H1/p115 RhoGEF (Ser284-dependent), and ROCK2 forms a complex with JAM-A to regulate lymphatic junction tension; (4) controls epithelial polarity and spindle orientation by activating Cdc42/PI(3)K to localize dynactin cortically; (5) inhibits integrin αIIbβ3 outside-in signaling in platelets while being processed by ADAM17 in aging endothelium; and (6) initiates Hippo signaling (via NF2/LATS1) to suppress intestinal epithelial proliferation and participates in a CD9/CD81/αvβ5 integrin complex to enforce contact inhibition of locomotion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"F11R/JAM-A is an immunoglobulin-superfamily transmembrane adhesion receptor of endothelial and epithelial junctions, platelets, and leukocytes that converts adhesive engagement into intracellular signaling to control leukocyte trafficking, junctional barrier function, epithelial polarity, and cell proliferation [#0, #6, #14]. Through its extracellular Ig domains it engages two adhesive modes: a homophilic trans-interaction stabilized by the second Ig domain and a stronger heterophilic interaction with the \\u03b22 integrin LFA-1, whose binding to domain 2 cancels homophilic stabilization and drives leukocyte adhesion and transendothelial migration [#0, #9]; trans-dimerization requires residues 43NNP45 and activates Rap2 signaling [#17]. In inflamed endothelium JAM-A is transcriptionally induced via NF-\\u03baB and JAK/STAT and inserted on the luminal surface to support platelet adhesion, and acts sequentially with ICAM-2 and PECAM-1 to mediate stimulus-specific leukocyte transmigration [#31, #10, #5]. At junctions JAM-A nucleates a ZO-2/afadin/PDZ-GEF1 complex that activates Rap2c and tunes RhoA-dependent actomyosin contraction to restrict paracellular permeability [#14], and drives a C/EBP-\\u03b1-dependent transcriptional program that upregulates claudin-5 to tighten endothelial barriers [#22]. Barrier control is gated by phosphorylation: aPKC phosphorylates Ser285 to promote junction maturation and single-lumen specification (reversed by PP2A) [#12], while Yes-1-mediated Y280 phosphorylation, opposed by PTPN13, uncouples JAM-A from active Rap2 and disrupts the barrier during cytokine exposure [#20]. JAM-A also functions as a mechanosensor, with tension activating RhoA through GEF-H1 and p115 RhoGEF in a Ser284-dependent manner, and its loss redistributing tension to a p114RhoGEF/ZO-1 axis [#19, #23]. In epithelia it restrains proliferation in a dimerization-dependent manner by inhibiting Akt/\\u03b2-catenin signaling and by engaging the Hippo pathway through NF2 and LATS1 to suppress YAP activity [#11, #26], and it orients the mitotic spindle by triggering Cdc42/PI(3)K signaling to localize cortical dynactin [#18]. In platelets JAM-A acts as an endogenous inhibitor of integrin \\u03b1IIb\\u03b23 outside-in signaling [#13], and at cell contacts it assembles with tetraspanins CD9/CD81 and \\u03b1v\\u03b25 integrin, binding Csk to suppress Src and enforce contact inhibition of locomotion [#28]. JAM-A additionally serves as a strain-specific rotavirus coreceptor whose use is determined by viral VP4 [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established JAM-A as an adhesive receptor with defined ligands, resolving how a junctional Ig-superfamily protein mediates both leukocyte trafficking and platelet adhesion.\",\n      \"evidence\": \"JAM-1 transfection with LFA-1-dependent adhesion/transmigration assays and domain deletion; platelet adhesion to inflamed endothelium blocked by soluble F11R and domain peptides\",\n      \"pmids\": [\"11812992\", \"12428104\", \"12008956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the LFA-1 binding interface not defined here\", \"Relative in vivo contribution of homophilic vs heterophilic engagement unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed JAM-A engages integrin partners and signals via its cytoplasmic domain, linking adhesion to MAP kinase and angiogenic responses.\",\n      \"evidence\": \"Co-IP of JAM-1/\\u03b1v\\u03b23, cytoplasmic domain mutagenesis, and endothelial tube formation assays\",\n      \"pmids\": [\"12750158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of \\u03b1v\\u03b23 association not defined\", \"Cytoplasmic effectors linking JAM-A to MAPK not identified in this study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the in vivo physiological roles of JAM-A in leukocyte transmigration and intestinal barrier function using genetic loss-of-function.\",\n      \"evidence\": \"Intravital microscopy and barrier assays in JAM-A knockout mice plus antibody blockade and siRNA, with PECAM-1 epistasis and claudin expression analysis\",\n      \"pmids\": [\"17505016\", \"18039951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling endothelial JAM-A to transmigration step not molecularly resolved\", \"How JAM-A loss raises claudin-10/-15 expression not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Quantified the competition between homophilic and heterophilic adhesion and revealed JAM-A's cell-autonomous role in integrin recycling during chemotaxis.\",\n      \"evidence\": \"Atomic force microscopy adhesion measurements with domain mutants; JAM-A-null neutrophil chemotaxis with \\u03b21-integrin co-clustering and internalization assays; triple-KO intravital epistasis\",\n      \"pmids\": [\"18849408\", \"19118219\", \"19211506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor linking JAM-A to \\u03b21-integrin endosomal trafficking not identified\", \"Hierarchy of ICAM-2/JAM-A/PECAM-1 across stimuli not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the phospho-regulatory code of the cytoplasmic tail, with aPKC/PP2A acting on Ser285 to control junction maturation and lumen specification.\",\n      \"evidence\": \"Direct aPKC-JAM-A binding, S285A phosphomutant, PP2A identification, and 3D cyst morphogenesis assays\",\n      \"pmids\": [\"22371556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of Ser285 phosphorylation not fully defined\", \"Interplay with other tail phosphosites not addressed here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established JAM-A as a dimerization-dependent brake on epithelial proliferation via Akt/\\u03b2-catenin inhibition, connecting adhesion to growth control.\",\n      \"evidence\": \"JAM-A KO mice with \\u03b2-catenin/TCF reporter, Akt inhibitor rescue, and dimerization-deficient mutant expression\",\n      \"pmids\": [\"21372850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from JAM-A dimerization to Akt not defined\", \"Cell-type generality of the proliferation control untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the junctional signaling complex through which JAM-A activates Rap2c and tunes actomyosin contraction to set paracellular permeability.\",\n      \"evidence\": \"Co-IP defining direct ZO-2 and indirect afadin binding, PDZ-GEF1/Rap2c activation, siRNA epistasis, and RhoA/myosin assays\",\n      \"pmids\": [\"23885123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the ZO-2/afadin/PDZ-GEF1 complex not defined\", \"How Rap2c output feeds back on RhoA not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Separated cis- from trans-dimerization interfaces and showed trans-dimerization is the signaling-competent mode coupling cell confluence to Rap2 activity; identified JAM-A as a strain-specific rotavirus coreceptor.\",\n      \"evidence\": \"Distinct-interface alanine mutants with AFM and Rap2 assays; antibody/siRNA blocking with VP4 reassortant virus analysis\",\n      \"pmids\": [\"24672055\", \"25481868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NNP-mediated trans-dimerization not solved\", \"VP4 region contacting JAM-A not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined JAM-A's role in mitotic spindle orientation, extending its function from junction maintenance to oriented epithelial morphogenesis.\",\n      \"evidence\": \"JAM-A loss-of-function with live spindle imaging, Cdc42/PI(3)K activity assays, dynactin localization, and 3D cyst culture\",\n      \"pmids\": [\"26306570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JAM-A triggers transient Cdc42 activation at the cortex not resolved\", \"Link between PtdIns(3,4,5)P3 gradient and dynactin recruitment not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established JAM-A as a tension-sensing receptor that activates RhoA through GEF-H1/p115 RhoGEF in a Ser284-dependent manner.\",\n      \"evidence\": \"Antibody-bead tension application, RhoA assays, kinase inhibitors, S284 phosphomutant, and GEF siRNA\",\n      \"pmids\": [\"26985018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Force-sensing structural element of JAM-A not identified\", \"Relationship between Ser284 (tension) and Ser285 (aPKC) phosphorylation not reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Completed the tyrosine phospho-switch for barrier control by identifying Yes-1 and PTPN13 as the Y280 kinase/phosphatase pair that gates JAM-A\\u2013Rap2 coupling under inflammation, and placed JAM-A within tight-junction strand assembly genetically.\",\n      \"evidence\": \"Phospho-specific antibodies, Yes-1/PTPN13 siRNA, Src inhibitor, Rap2 assays, colitis models; systematic genome-edited combinatorial KO of TJ components with EM\",\n      \"pmids\": [\"30625033\", \"31467165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between Y280 and Ser285/Ser284 phosphorylation events not integrated\", \"Direct structural role of JAM-A in strand assembly versus claudins not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the transcriptional and mechanical outputs of JAM-A barrier control: a C/EBP-\\u03b1\\u2192claudin-5 program and a p114RhoGEF/ZO-1 tension axis engaged upon JAM-A loss.\",\n      \"evidence\": \"JAM-A KO mice with C/EBP-\\u03b1 gain/loss and ChIP at the claudin-5 promoter; ZO-1 FRET tension sensor and traction force microscopy with p114RhoGEF knockdown on variable-stiffness substrates\",\n      \"pmids\": [\"32673519\", \"32697990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JAM-A activates EPAC upstream of C/EBP-\\u03b1 not mechanistically detailed\", \"Trigger that recruits p114RhoGEF upon JAM-A depletion not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected JAM-A to the Hippo pathway and to tetraspanin/integrin complexes that enforce contact inhibition and direct collective migration.\",\n      \"evidence\": \"Co-IP of JAM-A with NF2/LATS1 and dimerization-null mutant epistasis with YAP readout; co-IP/domain mapping of CD9/CD81/\\u03b1v\\u03b25 and \\u03b13\\u03b21/CD151/CD9 complexes with Csk pulldown, Src/Rac1 assays, and CIL/migration assays\",\n      \"pmids\": [\"35602956\", \"35293964\", \"35067832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs scaffolded nature of JAM-A\\u2013NF2/LATS1 interaction not resolved\", \"How tetraspanin complexes are spatially coordinated with junctional JAM-A pools unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed a cytokine-induced ROCK2/JAM-A complex tightens lymphatic junctions and impairs drainage, with genetic ROCK2 deletion reversing lymphedema.\",\n      \"evidence\": \"Microfluidic lymphatic drainage-on-chip, ROCK2/JAM-A co-IP, ROCK inhibition, and lymphatic-specific ROCK2 conditional KO mice\",\n      \"pmids\": [\"37782785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ROCK2/JAM-A interaction not defined\", \"How this complex relates to the GEF-H1/p115 tension pathway not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple JAM-A cytoplasmic phosphorylation events (Ser284, Ser285, Y280, Thr273) and competing GEF/integrin/tetraspanin partners are integrated into a single context-dependent output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling distinct phosphosites to barrier, mechanics, and proliferation outputs\", \"Structural details of trans-dimer and partner complexes largely undefined\", \"Tissue-specific selection among competing effector pathways not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 9, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 19, 23, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 28]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 26, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 7, 31]},\n      {\"term_id\": \"GO:0005923\", \"supporting_discovery_ids\": [14, 21, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 19, 22, 26]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 13, 31]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [14, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 18, 33]}\n    ],\n    \"complexes\": [\n      \"JAM-A/ZO-2/afadin/PDZ-GEF1 junctional complex\",\n      \"JAM-A/CD9/CD81/\\u03b1v\\u03b25 integrin complex\",\n      \"JAM-A/\\u03b13\\u03b21/CD151/CD9 complex\",\n      \"JAM-A/CASK/PMCA4b sperm flagellar complex\"\n    ],\n    \"partners\": [\n      \"ITGAL\",\n      \"ZO-2\",\n      \"afadin\",\n      \"ITGAV\",\n      \"CD9\",\n      \"PTPN13\",\n      \"NF2\",\n      \"ROCK2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}