{"gene":"F11R","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2002,"finding":"JAM-A (F11R/JAM-1) functions as a ligand for the β2 integrin LFA-1, mediating LFA-1-dependent transendothelial migration of T cells and neutrophils; the interaction requires the membrane-proximal Ig-like domain 2 of JAM-A.","method":"Adhesion assays under static and physiological flow conditions, transfectant expression of JAM-A, domain deletion mutants","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (transfectants, flow assays, domain mutants), replicated in multiple cell types","pmids":["11812992"],"is_preprint":false},{"year":2001,"finding":"Human JAM-1 (F11R) localizes to cell-cell junctions via homophilic binding; recombinant JAM-1 expressed in CHO cells concentrates at contacts between two transfected cells (not between transfected and untransfected cells), and human platelets specifically bind JAM-1-expressing CHO cell monolayers.","method":"Immunofluorescence of CHO transfectants, platelet adhesion assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization and adhesion assay, single lab, two orthogonal approaches","pmids":["11171323"],"is_preprint":false},{"year":2002,"finding":"F11R/JAM-A mediates adhesion of human platelets to cytokine-inflamed endothelial cells through homophilic interactions; the N-terminal region and the 1st Ig-fold of F11R are required, as shown by inhibition with recombinant soluble F11R and peptides spanning those domains.","method":"Platelet adhesion assays to immobilized recombinant sF11R and cytokine-stimulated HUVEC; inhibition with domain peptides","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — reciprocal inhibition with soluble protein and domain-specific peptides, multiple readouts","pmids":["12428104"],"is_preprint":false},{"year":2002,"finding":"Two regions of F11R (N-terminal S1–C23 and K70–C82 in the 1st Ig-fold) are critical for M.Ab.F11-induced platelet aggregation, secretion, potentiation, and adhesion; soluble recombinant F11R fully inhibits these responses.","method":"Platelet aggregation and adhesion assays with domain-specific peptides and recombinant sF11R; 3D structural modeling of active site","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1–2 — peptide mapping with functional assays plus structural modeling, multiple readouts","pmids":["12008956"],"is_preprint":false},{"year":2003,"finding":"JAM-1/A and integrin αvβ3 form a complex in quiescent endothelial cells; bFGF signaling dissociates this complex, redistributes JAM-1 to the cell surface, and requires signaling through the JAM-1 cytoplasmic domain for MAP kinase activation and tube formation.","method":"Co-immunoprecipitation, JAM-1 cytoplasmic domain mutations, MAP kinase activation assays, endothelial tube formation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — co-IP plus mutagenesis plus functional angiogenesis assay in single study","pmids":["12750158"],"is_preprint":false},{"year":2004,"finding":"M.Ab.F11-mediated F11R signaling in platelets requires crosslinking of F11R with FcγRII, leading to actin filament assembly (PI3K-dependent, wortmannin-sensitive), increased intracellular calcium, phosphorylation of F11R (32 and 35 kDa forms), F11R dimerization, and association of F11R with integrin GPIIIa and CD9.","method":"Platelet activation assays, PI3K inhibition (wortmannin), co-immunoprecipitation of F11R with GPIIIa and CD9, calcium measurement, phosphorylation analysis","journal":"Journal of receptor and signal transduction research","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical methods (co-IP, phosphorylation, Ca2+ measurement, inhibitor studies) in single study","pmids":["15344881"],"is_preprint":false},{"year":2004,"finding":"JAM-1 is recruited to cell-cell contacts in the mouse preimplantation embryo during the 8-cell stage (earlier than any other TJ protein analyzed), transiently localizes to the apical pole during compaction with PKCζ and PKCδ, and anti-JAM-1 neutralizing antibodies delay blastocoel cavity formation by impairing the TJ paracellular seal without affecting global embryo compaction.","method":"Immunofluorescence confocal microscopy of staged embryos, neutralizing antibody treatment with functional readout (blastocoel formation)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional antibody-blocking experiment in intact embryos","pmids":["15494378"],"is_preprint":false},{"year":2007,"finding":"Endothelial-cell JAM-A (but not leukocyte JAM-A) mediates neutrophil transmigration in response to IL-1β and ischemia/reperfusion injury in vivo; JAM-A and PECAM-1 act sequentially (not additively) to mediate transmigration.","method":"Intravital microscopy in JAM-A KO and neutralizing antibody-treated mice; leukocyte transfer to JAM-A-deficient endothelium; dual JAM-A/PECAM-1 blockade","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus antibody blockade plus cell-transfer epistasis experiment in vivo","pmids":["17505016"],"is_preprint":false},{"year":2007,"finding":"JAM-A is present in the plasma membrane of the head and flagellum of mouse spermatozoa; deletion of Jam-A causes flagellar ultrastructural defects, reduced progressive and hyperactivated motility before and after capacitation, and reduced litter size.","method":"Gene trap knockout, transmission electron microscopy, sperm motility analysis (CASA), immunofluorescence","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with ultrastructural and functional phenotypic readouts","pmids":["18022613"],"is_preprint":false},{"year":2007,"finding":"JAM-A is a cell-surface marker exclusively on long-term repopulating hematopoietic stem cells (LTR-HSC); JAM-A+ cells sorted from whole bone marrow are highly enriched for LTR-HSC activity in transplantation assays.","method":"Flow cytometric sorting, colony-forming assays, competitive bone marrow transplantation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — direct functional enrichment by transplantation, multiple hematopoietic tissues tested","pmids":["17986666"],"is_preprint":false},{"year":2009,"finding":"JAM-A on neutrophils concentrates at the leading edge and uropod; a significant fraction is internalized into endosomal-like vesicles co-distributing with β1 integrin. In JAM-A-null neutrophils, β1 integrin internalization upon chemotactic stimuli is impaired, causing defective uropod retraction and reduced directional migration.","method":"Intravital microscopy, in vitro chemotaxis assays with JAM-A-null neutrophils, co-clustering experiments, BAPTA-AM integrin internalization inhibition","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic null plus pharmacological inhibition plus co-localization, in vivo and in vitro readouts","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 stabilizes the homophilic bond, and LFA-1 binding to domain 2 reduces homophilic bond strength to that of a domain-2 deletion mutant. The LFA-1/JAM-A heterophilic interaction is stronger than the JAM-A homophilic interaction.","method":"Atomic force microscopy adhesion measurements, competitive binding assays, domain deletion mutants of JAM-A","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 — direct biophysical force measurements with domain mutants, quantitative competition assays","pmids":["18849408"],"is_preprint":false},{"year":2009,"finding":"ICAM-2, JAM-A, and PECAM-1 act sequentially to mediate neutrophil transmigration through mouse cremasteric venules in a stimulus-dependent manner; when TNF-α directly stimulates neutrophils, these molecules are dispensable, but when neutrophil TNFR signaling is blocked, transmigration becomes dependent on all three endothelial molecules in sequence.","method":"Intravital microscopy, cell transfer with TNFR-KO leukocytes into ICAM-2/JAM-A/PECAM-1 KO recipient mice, site-of-arrest analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — epistasis via genetic KO combinations and cell transfer, in vivo imaging","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 mice show enhanced β-catenin/TCF transcription and colonic crypt hyperproliferation reversible by Akt inhibition.","method":"JAM-A KO mice crossed to β-catenin/TCF reporter mice, Akt inhibitor rescue of hyperproliferation, in vitro dimerization-deficient mutant studies","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with pharmacological rescue, in vivo and in vitro validation of signaling pathway","pmids":["21372850"],"is_preprint":false},{"year":2012,"finding":"aPKC directly interacts with JAM-A in a PAR-3-independent manner and phosphorylates JAM-A at Ser285 upon recruitment to primordial junctions. S285-phosphorylated JAM-A localizes exclusively to tight junctions in polarized cells; S285 phosphorylation is required for functional epithelial barrier formation and single lumen specification in 3D culture. Protein phosphatase 2A dephosphorylates JAM-A at S285.","method":"In vitro kinase assay, phospho-specific antibodies, non-phosphorylatable JAM-A/S285A mutant expression, 3D cyst culture, PP2A inhibition","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation assay with mutagenesis plus functional TJ and polarity readouts","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 enhanced platelet spreading and clot retraction (outside-in), but normal inside-out signaling (granule secretion, TxA2 generation, fibrinogen receptor activation), resulting in enhanced thrombotic function in vivo.","method":"Jam-A KO mice, platelet spreading and clot retraction assays (outside-in), granule secretion and aggregation assays (inside-out), intravital thrombosis models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with mechanistic dissection of inside-out vs. outside-in signaling using multiple functional assays","pmids":["22271446"],"is_preprint":false},{"year":2012,"finding":"On the sperm flagellum, CASK interacts via its PDZ domain alternatively and non-synergistically with either JAM-A or PMCA4b. In the absence of JAM-A, CASK-PMCA4b interaction increases, inhibiting PMCA4b enzymatic activity, causing Ca2+ accumulation and reduced ATP, thus impairing motility. JAM-A positively regulates PMCA4b indirectly through CASK.","method":"Co-immunoprecipitation, PMCA4b enzymatic activity assay, Ca2+ and ATP measurements in Jam-A null sperm","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 — co-IP plus enzymatic activity measurement plus ion/energy metabolite assays in genetic KO","pmids":["22020416"],"is_preprint":false},{"year":2013,"finding":"JAM-A associates directly with ZO-2 and indirectly with afadin; this complex together with PDZ-GEF1 activates the small GTPase Rap2c to regulate epithelial barrier function. siRNA knockdown of each component phenocopies JAM-A loss (enhanced permeability). JAM-A also modulates RhoA activity and non-muscle myosin phosphorylation to control perijunctional actomyosin contraction.","method":"Co-immunoprecipitation, siRNA knockdown of complex components, GTPase activity assays (Rap2c, RhoA), permeability assays, JAM-A KO mice","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, epistasis by siRNA, GTPase biochemistry, in vivo KO validation","pmids":["23885123"],"is_preprint":false},{"year":2014,"finding":"Trans-dimerization of JAM-A (between adjacent cell surfaces) occurs at a distinct domain from cis-dimerization; residues 43NNP45 in the predicted trans-dimerization site are required. Trans- but not cis-null JAM-A mutants decrease Rap2 activity, and confluent cells (enabling trans-dimerization) show enhanced Rap2 activity, identifying trans-dimerization as a barrier-inducing molecular switch.","method":"Transfection of cis- and trans-null JAM-A alanine mutants, microsphere aggregation assays, atomic force microscopy, Rap2 GTPase activity assays, cell confluence experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — AFM force measurements, domain-specific mutagenesis, GTPase signaling assays, multiple orthogonal approaches","pmids":["24672055"],"is_preprint":false},{"year":2014,"finding":"JAM-A serves as a coreceptor for rotavirus entry into MA104 cells; the viral spike protein VP4 determines use of JAM-A as coreceptor, and JAM-A is required for infection by rotavirus strains RRV, Wa, and UK but not YM.","method":"Antibody blocking, RRV/YM reassortant virus analysis determining VP4 as the viral determinant, infection assays in MA104 cells","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 — genetic reassortant analysis plus antibody blocking identifies viral and host determinants","pmids":["25481868"],"is_preprint":false},{"year":2015,"finding":"JAM-A regulates planar orientation of the mitotic spindle in polarized epithelial cells by triggering transient Cdc42 and PI(3)K activation, generating a cortical PtdIns(3,4,5)P3 gradient and regulating cortical actin; in the absence of functional JAM-A, dynactin localization at the lateral cortex is reduced and the mitotic spindle is misaligned.","method":"JAM-A KO/functional mutant cells, live imaging of spindle orientation, PI(3)K and Cdc42 activity measurements, dynactin localization by immunofluorescence, 3D cyst morphogenesis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic loss of function with mechanistic signaling dissection (Cdc42, PI3K, PIP3 gradient) and direct dynactin localization","pmids":["26306570"],"is_preprint":false},{"year":2016,"finding":"Mechanical tension imposed on JAM-A activates RhoA via PI3K-dependent activation of GEF-H1 and p115 RhoGEF (further 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":"Magnetic bead tension assay on JAM-A, RhoA FRET biosensor, PI3K/FAK/ERK/Src kinase inhibitors, JAM-A Ser284 phospho-mutant expression","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — direct mechanotransduction assay with pharmacological and mutagenesis dissection of pathway","pmids":["26985018"],"is_preprint":false},{"year":2019,"finding":"During intestinal inflammation, the Src kinase Yes-1 phosphorylates JAM-A at Y280 (cytoplasmic tail), reducing JAM-A association with active Rap2 and impairing barrier function; PTPN13 is the major phosphatase for p-JAM-A Y280. Src kinase inhibitor PP2 rescues cytokine-induced barrier defects. Y280 phosphorylation is increased in ulcerative colitis patient colonic epithelium.","method":"Phospho-specific antibodies, kinase/phosphatase siRNA knockdown, co-immunoprecipitation with Rap2, Src inhibitor rescue, human colitis tissue analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — identified writer (Yes-1) and eraser (PTPN13) with functional rescue plus signaling link to Rap2, human tissue validation","pmids":["30625033"],"is_preprint":false},{"year":2019,"finding":"Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity; simultaneous deletion of claudins and JAM-A causes loss of membrane appositions, macromolecule permeability barrier, and sporadic epithelial polarity defects, whereas deletion of either alone does not fully recapitulate these phenotypes.","method":"Systematic genome editing (CRISPR) of TJ components in epithelial cells; TJ strand ultrastructure, permeability assays, polarity markers","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — combinatorial CRISPR KO epistasis with functional barrier and polarity readouts","pmids":["31467165"],"is_preprint":false},{"year":2020,"finding":"JAM-A promotes claudin-5 expression via C/EBP-α transcription factor; JAM-A suppresses β-catenin transcriptional activity and activates EPAC, which increases C/EBP-α expression; C/EBP-α then directly binds the claudin-5 promoter to promote transcription, thereby reducing endothelial permeability.","method":"JAM-A KO mice (vascular permeability assays), C/EBP-α gain/loss-of-function, FITC-dextran permeability, β-catenin inhibition, EPAC activation, chromatin studies of claudin-5 promoter, human glioblastoma/ovarian cancer tissue analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus multiple gain/loss-of-function experiments establishing the full JAM-A→EPAC→C/EBP-α→claudin-5 pathway with direct promoter binding","pmids":["32673519"],"is_preprint":false},{"year":2020,"finding":"JAM-A depletion stimulates junctional recruitment of p114RhoGEF/ARHGEF18, increases mechanical tension on ZO-1 (detected by a ZO-1 tension sensor), and increases traction forces at focal adhesions. p114RhoGEF is required for junctional actomyosin activity and TJ integrity on stiff but not soft ECM, placing JAM-A upstream of p114RhoGEF in mechanosensing.","method":"FRET-based ZO-1 tension sensor, traction force microscopy, JAM-A depletion, p114RhoGEF knockdown, variable stiffness ECM substrates","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — direct tension measurement with FRET sensor plus traction force microscopy and genetic epistasis","pmids":["32697990"],"is_preprint":false},{"year":2021,"finding":"ADAM17 cleaves JAM-A/F11R at the endothelial junction (at V232, identified by cleavage-resistant mutant JAM-AV232Y) in aged mice and cells exposed to reduced shear stress; loss of junctional JAM-A impairs endothelial wall shear stress mechanosensing, leading to inward hypertrophic arterial remodeling. Overexpression of ADAM17-cleavage-resistant JAM-AV232Y normalizes mechanosensing in aged resistance arteries.","method":"AAV9-mediated ADAM17 overexpression in young mice, JAM-A knockdown, cleavage-resistant JAM-AV232Y mutant rescue in vitro and in vivo, shear stress mechanosensing assays in aged mice","journal":"GeroScience","confidence":"High","confidence_rationale":"Tier 2 — identified ADAM17 as writer/sheddase with specific cleavage-resistant mutant rescue in vivo","pmids":["34718985"],"is_preprint":false},{"year":2022,"finding":"JAM-A interacts with α3β1 integrin and tetraspanins CD151 and CD9 through its extracellular domain to regulate collective cell migration of polarized epithelial cells on laminin and collagen-I substrates; depletion of JAM-A reduces cryptic lamellipodia dynamics in the collective, while JAM-A depletion enhances motility of single cells.","method":"MDCK cell JAM-A/integrin/tetraspanin depletion, co-immunoprecipitation, domain mapping, live-cell migration assays, substrate specificity experiments","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with domain mapping plus functional migration assays with multiple KD conditions","pmids":["35067832"],"is_preprint":false},{"year":2022,"finding":"JAM-A forms a multimolecular complex with tetraspanins CD9/CD81 and αvβ5 integrin; JAM-A binds Csk and inhibits αvβ5 integrin-associated Src activity. Loss of JAM-A increases Src downstream signaling (Erk1/2, Abi1, paxillin, Rac1 at cell contacts), increases cell-matrix turnover, and impairs contact inhibition of locomotion (CIL).","method":"Co-immunoprecipitation, Src/Erk/Rac1 activity assays, JAM-A KD with CIL functional assay, αvβ5 integrin engagement experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP establishing complex, kinase activity assays, genetic KD with defined CIL phenotype","pmids":["35293964"],"is_preprint":false},{"year":2022,"finding":"JAM-A interacts with NF2 and LATS1 to function as an initiator of the Hippo signaling pathway; JAM-A dimerization is required since a dimerization-deficient mutant (JAM-A-DL1) fails to activate Hippo and phenocopies JAM-A deficiency. JAM-A loss or DL1 expression increases YAP activity and EVI1 transcription factor expression to drive intestinal epithelial proliferation.","method":"Co-immunoprecipitation (JAM-A with NF2/LATS1), YAP activity assays, dimerization-deficient mutant expression, siRNA knockdown, EVI1 expression analysis in JAM-A KO IEC","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — co-IP identifying pathway components, mutagenesis showing dimerization dependence, downstream signaling validation","pmids":["35602956"],"is_preprint":false},{"year":2023,"finding":"In lymphatic endothelial cells, inflammatory cytokines induce formation of a ROCK2/JAM-A complex that tightens lymphatic cell-cell junctions and impedes lymphatic drainage; ROCK inhibition loosens lymphatic junctions. Lymphatic-specific ROCK2 knockout reversed lymphedema in mice in vivo.","method":"Microfluidic lymphatic-on-chip, co-immunoprecipitation of ROCK2 with JAM-A, ROCK isoform characterization, ROCK2 conditional KO mouse model with lymphedema readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — co-IP identifying ROCK2/JAM-A complex, in vitro chip model plus in vivo conditional KO rescue","pmids":["37782785"],"is_preprint":false},{"year":2013,"finding":"F11R mRNA levels are increased under hypoxia via ADAR1-mediated RNA editing of the 3'UTR; hyper-edited mature F11R mRNAs are retained in the nucleus via association with p54nrb, preventing cytoplasmic export and translation.","method":"RNA editing analysis under hypoxia, ADAR1/ADAR2 siRNA knockdown, nuclear/cytoplasmic fractionation, p54nrb RNA immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ADAR1 identified by knockdown, p54nrb interaction by RIP, fractionation showing nuclear retention; single lab","pmids":["24147060"],"is_preprint":false},{"year":2010,"finding":"F11R is expressed in smooth muscle cells of atherosclerotic arterial intima (not in normal media SMCs); cytokine stimulation induces F11R expression in cultured SMCs, and siRNA silencing of F11R blocks both migration and proliferation of inflamed SMCs.","method":"Immunofluorescence of human atherosclerotic arteries, RT-PCR and Western blot in cytokine-stimulated SMCs, siRNA knockdown with migration/proliferation assays","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 3 — KD with defined cellular phenotype in vitro, human tissue localization; single lab","pmids":["20627246"],"is_preprint":false},{"year":2011,"finding":"De novo transcription and translation of F11R in endothelial cells, induced by TNF-α/IFN-γ via NF-κB and JAK/STAT pathways, is required for adhesion of human platelets to inflamed endothelium; siRNA silencing of F11R mRNA completely blocks cytokine-induced F11R protein upregulation and platelet adhesion.","method":"Transcription/translation inhibitors (actinomycin, parthenolide, AG-480), F11R siRNA knockdown in HUVEC, platelet adhesion assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 — siRNA knockdown with functional platelet adhesion readout; pathway placement via signaling inhibitors; single lab","pmids":["21703019"],"is_preprint":false},{"year":2007,"finding":"JAM-A regulates permeability and inflammation in the intestinal epithelium; JAM-A-deficient mice show increased mucosal permeability (dextran flux, reduced TER) and altered expression of claudin-10 and claudin-15 in colonic mucosa. JAM-A loss also increases susceptibility to DSS-induced colitis with enhanced epithelial proliferation.","method":"JAM-A KO mice, dextran flux and TER measurements, immunoblot for claudins in KO vs. WT, JAM-A siRNA in epithelial monolayers, DSS colitis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple barrier readouts, claudin expression changes validated in vitro by siRNA, in vivo disease model","pmids":["18039951"],"is_preprint":false},{"year":2022,"finding":"JAM-A expression transcriptionally regulates HER2 by influencing binding of the transcription factor FOXA1 to a specific site in the HER2 gene promoter in breast cancer cells.","method":"JAM-A knockdown with FOXA1 ChIP at HER2 promoter, HER2 expression rescue experiments, promoter reporter assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP at defined promoter region with genetic perturbation; single lab","pmids":["35203384"],"is_preprint":false},{"year":2008,"finding":"Nectin-3 (via its effector afadin) enables 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":"Co-expression of adhesion molecules in L fibroblasts lacking TJs/AJs, immunofluorescence co-localization, afadin requirement demonstrated","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 3 — reconstitution in fibroblast system with defined component requirements; single lab","pmids":["18547333"],"is_preprint":false}],"current_model":"F11R/JAM-A is a multifunctional immunoglobulin-superfamily transmembrane protein that (1) forms homophilic cis- and trans-dimers and heterophilic complexes with LFA-1, αvβ3, αIIbβ3, α3β1 integrin, αvβ5 integrin, tetraspanins CD9/CD81/CD151, and intracellular scaffolds ZO-2/afadin/PDZ-GEF1; (2) is phosphorylated at Ser285 by aPKC (promoting TJ maturation and dephosphorylated by PP2A) and at Tyr280 by Src kinase Yes-1 (impairing barrier via reduced Rap2 activity, reversed by PTPN13); (3) signals through Rap2c, RhoA (via GEF-H1/p115 RhoGEF in response to tension), Cdc42/PI(3)K (for planar spindle orientation), Akt/β-catenin (restraining proliferation), and the Hippo pathway (via NF2/LATS1/YAP to suppress proliferation); (4) regulates endothelial barrier by promoting C/EBP-α-driven claudin-5 transcription downstream of EPAC; (5) is shed by ADAM17 to generate soluble JAM-A that modulates thrombo-inflammation; and (6) acts as a receptor for reovirus entry (via VP4-dependent interaction) and as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling in platelets."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that F11R/JAM-A mediates cell-cell adhesion through homophilic binding answered the question of how this Ig-superfamily protein concentrates at intercellular junctions and supports platelet-endothelial contact.","evidence":"Immunofluorescence of CHO transfectants showing JAM-1 concentration only at transfected–transfected cell contacts; platelet adhesion assay","pmids":["11171323"],"confidence":"Medium","gaps":["Single lab; no biophysical measurement of binding affinity","Cis- vs. trans-dimerization not distinguished"]},{"year":2002,"claim":"Identification of JAM-A as a heterophilic ligand for LFA-1 (via Ig domain 2) and mapping of homophilic adhesion sites (N-terminal and first Ig fold) established the dual-mode adhesive logic underlying JAM-A's roles in leukocyte transmigration and platelet adhesion.","evidence":"Adhesion assays under flow with domain-deletion mutants (LFA-1); peptide/soluble-protein inhibition of platelet aggregation and adhesion to HUVEC","pmids":["11812992","12428104","12008956"],"confidence":"High","gaps":["No crystal structure of the JAM-A/LFA-1 interface","Relative contribution of homophilic vs. heterophilic interactions during in vivo transmigration unknown"]},{"year":2003,"claim":"Discovery that JAM-A forms a complex with integrin αvβ3 in quiescent endothelium—dissociated by bFGF signaling to activate MAPK—established JAM-A as a signaling scaffold that couples junctional state to angiogenic responses.","evidence":"Co-immunoprecipitation, JAM-A cytoplasmic-domain mutants, MAP kinase assays, endothelial tube formation","pmids":["12750158"],"confidence":"High","gaps":["Direct binding interface between JAM-A and αvβ3 not mapped","Downstream mechanism linking cytoplasmic domain to MAPK not defined"]},{"year":2004,"claim":"Demonstration that JAM-A is the earliest tight-junction protein recruited to cell-cell contacts in the preimplantation embryo (8-cell stage), colocalizing with aPKC, and that its blockade delays blastocoel formation established a role in the very first polarization and sealing event in mammalian development.","evidence":"Confocal immunofluorescence of staged mouse embryos; neutralizing-antibody functional assay","pmids":["15494378"],"confidence":"High","gaps":["Molecular basis of early recruitment (before other TJ proteins) not elucidated","aPKC-JAM-A phosphorylation relationship not yet tested at this stage"]},{"year":2007,"claim":"In vivo knockout and antibody-blockade studies resolved that endothelial (not leukocyte) JAM-A is the critical partner for neutrophil transmigration and acts sequentially with PECAM-1 and ICAM-2, while intestinal JAM-A loss increases mucosal permeability and susceptibility to colitis.","evidence":"Intravital microscopy in JAM-A KO mice with leukocyte transfer; DSS colitis model; barrier assays in KO intestine","pmids":["17505016","19211506","18039951"],"confidence":"High","gaps":["Signal from endothelial JAM-A that initiates the transmigration step not identified","Whether barrier defects are cell-autonomous vs. secondary to altered claudin expression not fully resolved"]},{"year":2007,"claim":"JAM-A KO spermatozoa display flagellar ultrastructural defects and reduced motility, revealing an unexpected role for JAM-A outside classical junctional contexts; JAM-A also marked long-term repopulating hematopoietic stem cells, broadening its functional territory.","evidence":"Gene-trap KO with TEM and CASA sperm motility analysis; competitive bone-marrow transplantation of JAM-A+ sorted cells","pmids":["18022613","17986666"],"confidence":"High","gaps":["Molecular mechanism linking JAM-A to flagellar structure unknown at this point","Functional role of JAM-A on HSCs (beyond marker) not tested"]},{"year":2009,"claim":"Biophysical AFM measurements showed that LFA-1 binding to JAM-A domain 2 destabilizes JAM-A homophilic bonds, providing the force-based mechanism by which leukocytes open junctions; concurrently, JAM-A was shown to regulate β1-integrin internalization in neutrophils, linking it to directional migration.","evidence":"Atomic force microscopy with domain mutants; intravital microscopy and chemotaxis assays with JAM-A-null neutrophils","pmids":["18849408","19118219"],"confidence":"High","gaps":["Structural basis of LFA-1-induced destabilization not resolved at atomic level","Whether integrin internalization role generalizes beyond neutrophils untested"]},{"year":2011,"claim":"JAM-A was shown to restrain intestinal epithelial proliferation through dimerization-dependent suppression of Akt/β-catenin signaling, directly linking junctional adhesion to growth control.","evidence":"JAM-A KO mice crossed to β-catenin/TCF reporter; Akt inhibitor rescue of crypt hyperproliferation; dimerization-deficient mutants in vitro","pmids":["21372850"],"confidence":"High","gaps":["How JAM-A dimerization biochemically inhibits Akt not defined","Whether proliferation effect is Hippo-independent or feeds through it"]},{"year":2012,"claim":"aPKC was identified as the kinase phosphorylating JAM-A at Ser285 (dephosphorylated by PP2A), directing JAM-A to tight junctions and controlling single-lumen specification; separately, JAM-A was established as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling in platelets, and CASK was found to link JAM-A to PMCA4b regulation of flagellar Ca²⁺.","evidence":"In vitro kinase assays, S285A mutants in 3D cysts; Jam-A KO platelet spreading/clot retraction vs. inside-out assays; co-IP/PMCA4b activity in KO sperm","pmids":["22371556","22271446","22020416"],"confidence":"High","gaps":["aPKC recruitment mechanism to JAM-A (PAR-3-independent) not structurally explained","How JAM-A inhibits outside-in signaling at the molecular level unresolved"]},{"year":2013,"claim":"Identification of the ZO-2/afadin/PDZ-GEF1 scaffold and Rap2c as the GTPase downstream of JAM-A provided the first complete signaling module linking JAM-A to barrier regulation, complemented by RhoA/actomyosin control.","evidence":"Reciprocal co-IP, siRNA epistasis of each scaffold component, Rap2c and RhoA GTPase activity assays, JAM-A KO mice barrier measurements","pmids":["23885123"],"confidence":"High","gaps":["Stoichiometry and assembly order of the scaffold unknown","Whether Rap2c and RhoA arms are independent or cross-regulated not tested"]},{"year":2014,"claim":"Dissection of cis- versus trans-dimerization interfaces showed that trans-dimerization (residues 43NNP45) specifically activates Rap2 and induces barrier, establishing trans-dimerization as the contact-dependent molecular switch.","evidence":"Alanine scanning of cis/trans interfaces, AFM, microsphere aggregation, Rap2 GTPase assays in confluent vs. subconfluent cells","pmids":["24672055"],"confidence":"High","gaps":["No high-resolution structure of mammalian JAM-A trans-dimer confirming mutagenesis findings","Whether cis-dimerization has separable signaling outputs remains unclear"]},{"year":2015,"claim":"JAM-A was found to orient the mitotic spindle in polarized epithelia via transient Cdc42/PI3K activation and cortical PIP3 gradient generation, linking junctional adhesion to tissue architecture maintenance during cell division.","evidence":"JAM-A KO/functional mutant live imaging of spindle, PI3K/Cdc42 activity measurements, dynactin localization, 3D cyst morphogenesis","pmids":["26306570"],"confidence":"High","gaps":["How JAM-A activates Cdc42 transiently and locally not molecularly defined","Whether spindle orientation defect contributes to tumorigenesis not tested in vivo"]},{"year":2016,"claim":"Direct mechanical tension on JAM-A was shown to activate RhoA through PI3K-dependent GEF-H1 and p115RhoGEF (requiring Ser284 phosphorylation), establishing JAM-A as a junctional mechanosensor.","evidence":"Magnetic bead tension assay, RhoA FRET biosensor, kinase inhibitors, Ser284 phospho-mutant","pmids":["26985018"],"confidence":"High","gaps":["Identity of the kinase for Ser284 in the mechanosensing context not determined","Whether mechanotransduction feeds back to Rap2 signaling unclear"]},{"year":2019,"claim":"Src-family kinase Yes-1 was identified as the writer and PTPN13 as the eraser for JAM-A Tyr280 phosphorylation, which impairs Rap2 association and barrier function during inflammation—directly linking cytokine signaling to the JAM-A/Rap2 switch in ulcerative colitis tissue.","evidence":"Phospho-specific antibodies, siRNA of Yes-1/PTPN13, co-IP with Rap2, Src inhibitor rescue, human colitis tissue","pmids":["30625033"],"confidence":"High","gaps":["Structural basis of how Y280 phosphorylation disrupts Rap2 binding unknown","Whether Y280 and S285 phosphorylation events are coordinated or independent not tested"]},{"year":2020,"claim":"Two parallel downstream pathways of JAM-A were elaborated: (1) an EPAC/C/EBP-α axis that transcriptionally activates claudin-5 in endothelium, and (2) a mechanosensitive role upstream of p114RhoGEF/ZO-1 tension regulation that depends on substrate stiffness.","evidence":"JAM-A KO mice with vascular permeability assays, C/EBP-α gain/loss-of-function, ChIP on claudin-5 promoter; FRET ZO-1 tension sensor, traction force microscopy on variable-stiffness substrates","pmids":["32673519","32697990"],"confidence":"High","gaps":["Whether EPAC/C/EBP-α pathway operates in epithelia beyond endothelium untested","How JAM-A depletion triggers p114RhoGEF recruitment molecularly unresolved"]},{"year":2021,"claim":"ADAM17 was identified as the sheddase cleaving JAM-A at V232 in aged endothelium under low shear stress, with loss of junctional JAM-A impairing mechanosensing and causing inward arterial remodeling—linking JAM-A shedding to vascular aging.","evidence":"AAV9-ADAM17 overexpression in young mice, cleavage-resistant JAM-AV232Y mutant rescue in vivo, shear stress assays in aged arteries","pmids":["34718985"],"confidence":"High","gaps":["Whether soluble cleaved JAM-A ectodomain has signaling activity not addressed","Other sheddases that may contribute in non-endothelial contexts unknown"]},{"year":2022,"claim":"JAM-A was placed at the apex of Hippo signaling (via NF2/LATS1 interaction requiring dimerization) and as a Csk-recruiting inhibitor of αvβ5/Src signaling for contact inhibition of locomotion, while its extracellular domain was found to complex with α3β1 integrin and tetraspanins CD9/CD81/CD151 to regulate collective migration.","evidence":"Co-IP of JAM-A with NF2/LATS1, dimerization-deficient mutant phenocopy, YAP/EVI1 readouts; co-IP with Csk and αvβ5, Src/Erk/Rac1 activity in KD; co-IP with α3β1/CD151/CD9 and substrate-specific migration assays","pmids":["35602956","35293964","35067832"],"confidence":"High","gaps":["Whether Hippo and Akt/β-catenin pathways are redundant or additive in proliferation control unresolved","Structural basis of JAM-A–tetraspanin interaction not defined"]},{"year":2023,"claim":"ROCK2 was identified as a JAM-A partner in lymphatic endothelium where inflammation-induced ROCK2/JAM-A complex formation tightens junctions and impedes drainage, revealing a tissue-specific junctional-tightening mechanism distinct from the canonical barrier role.","evidence":"Co-IP of ROCK2 with JAM-A, microfluidic lymphatic chip, lymphatic-specific ROCK2 conditional KO reversing lymphedema in vivo","pmids":["37782785"],"confidence":"High","gaps":["Whether ROCK2 directly phosphorylates JAM-A in this context not tested","Generalizability to human lymphedema not established"]},{"year":null,"claim":"Key unresolved questions include: how the multiple phosphorylation events on JAM-A (Ser285, Tyr280, Ser284) are temporally coordinated during junction maturation and inflammation; the high-resolution structural basis of the JAM-A trans-dimer and its heterophilic complexes with integrins, tetraspanins, and Hippo components; whether JAM-A's anti-proliferative functions (Hippo vs. Akt/β-catenin) are synergistic or pathway-specific; and the in vivo significance of soluble JAM-A ectodomain generated by ADAM17 shedding.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated phospho-signaling model across Ser285/Tyr280/Ser284","No atomic-resolution structures of JAM-A heterophilic complexes","Functional significance of shed soluble JAM-A in vivo remains untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,3,11,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[17,28,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,28]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,6,8,14]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[8,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,10,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[14,17,18,23,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,20,21,22,29]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[3,5,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,34]}],"complexes":["ZO-2/afadin/PDZ-GEF1 scaffold","CD9/CD81/CD151 tetraspanin web","NF2/LATS1 Hippo complex","ROCK2/JAM-A lymphatic complex"],"partners":["ITGAL","ITGB3","ITGA3","CD9","TJP2","CASK","NF2","LATS1"],"other_free_text":[]},"mechanistic_narrative":"F11R (JAM-A) is an immunoglobulin-superfamily transmembrane protein that functions as a central organizer of tight-junction assembly, epithelial and endothelial barrier integrity, leukocyte transmigration, and platelet-endothelial adhesion. It forms homophilic cis- and trans-dimers through distinct domains in its two extracellular Ig folds, with trans-dimerization acting as a molecular switch that activates Rap2c via a ZO-2/afadin/PDZ-GEF1 scaffold complex to promote barrier function; aPKC phosphorylation at Ser285 drives JAM-A to mature tight junctions, while Src-family kinase Yes-1 phosphorylation at Tyr280 disrupts Rap2 association and impairs the barrier [PMID:22371556, PMID:24672055, PMID:23885123, PMID:30625033]. JAM-A serves as a heterophilic ligand for LFA-1 (via its membrane-proximal Ig domain 2), enabling sequential ICAM-2/JAM-A/PECAM-1-dependent neutrophil diapedesis, and acts as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling in platelets and of αvβ5-associated Src activity via Csk recruitment in epithelial cells [PMID:11812992, PMID:19211506, PMID:22271446, PMID:35293964]. Beyond adhesion, JAM-A controls epithelial proliferation through dimerization-dependent activation of the Hippo pathway (NF2/LATS1/YAP) and suppression of Akt/β-catenin signaling, regulates planar spindle orientation via Cdc42/PI3K-generated PIP3 gradients, promotes claudin-5 transcription through an EPAC/C/EBP-α axis in endothelium, and transduces mechanical tension into RhoA activation via GEF-H1 and p115RhoGEF [PMID:35602956, PMID:21372850, PMID:26306570, PMID:32697990, PMID:32673519, PMID:26985018]."},"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 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes.","date":"2002","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11812992","citation_count":499,"is_preprint":false},{"pmid":"18039951","id":"PMC_18039951","title":"JAM-A regulates permeability and inflammation in the intestine in vivo.","date":"2007","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18039951","citation_count":398,"is_preprint":false},{"pmid":"31467165","id":"PMC_31467165","title":"Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31467165","citation_count":179,"is_preprint":false},{"pmid":"19211506","id":"PMC_19211506","title":"Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19211506","citation_count":153,"is_preprint":false},{"pmid":"12750158","id":"PMC_12750158","title":"Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and alphavbeta3 complex.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12750158","citation_count":118,"is_preprint":false},{"pmid":"17505016","id":"PMC_17505016","title":"JAM-A mediates neutrophil transmigration in a stimulus-specific manner in vivo: evidence for sequential roles for JAM-A and PECAM-1 in neutrophil transmigration.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17505016","citation_count":112,"is_preprint":false},{"pmid":"23588236","id":"PMC_23588236","title":"Mast cell tryptase reduces junctional adhesion molecule-A (JAM-A) expression in intestinal epithelial cells: implications for the mechanisms of barrier dysfunction in irritable bowel syndrome.","date":"2013","source":"The American journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23588236","citation_count":107,"is_preprint":false},{"pmid":"32673519","id":"PMC_32673519","title":"JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/32673519","citation_count":103,"is_preprint":false},{"pmid":"23885123","id":"PMC_23885123","title":"JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23885123","citation_count":102,"is_preprint":false},{"pmid":"15494378","id":"PMC_15494378","title":"Contribution of JAM-1 to epithelial differentiation and tight-junction biogenesis in the mouse preimplantation embryo.","date":"2004","source":"Journal of cell 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/15681301","citation_count":78,"is_preprint":false},{"pmid":"21372850","id":"PMC_21372850","title":"JAM-A regulates epithelial proliferation through Akt/β-catenin signalling.","date":"2011","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/21372850","citation_count":77,"is_preprint":false},{"pmid":"6715885","id":"PMC_6715885","title":"Demonstration of species-specific and cross-reactive components of the adult microsomal antigens from Schistosoma mansoni and S. japonicum (MAMA and JAMA).","date":"1984","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6715885","citation_count":77,"is_preprint":false},{"pmid":"19118219","id":"PMC_19118219","title":"JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19118219","citation_count":75,"is_preprint":false},{"pmid":"25420915","id":"PMC_25420915","title":"JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals.","date":"2014","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/25420915","citation_count":72,"is_preprint":false},{"pmid":"33335797","id":"PMC_33335797","title":"Mesenchymal stem-cell-derived exosomal miR-145 inhibits atherosclerosis by targeting JAM-A.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33335797","citation_count":65,"is_preprint":false},{"pmid":"22271446","id":"PMC_22271446","title":"JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22271446","citation_count":65,"is_preprint":false},{"pmid":"27027514","id":"PMC_27027514","title":"JAM: A Scalable Bayesian Framework for Joint Analysis of Marginal SNP Effects.","date":"2016","source":"Genetic epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/27027514","citation_count":63,"is_preprint":false},{"pmid":"32697990","id":"PMC_32697990","title":"Interplay between Extracellular Matrix Stiffness and JAM-A Regulates Mechanical Load on ZO-1 and Tight Junction Assembly.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32697990","citation_count":59,"is_preprint":false},{"pmid":"18849408","id":"PMC_18849408","title":"LFA-1 binding destabilizes the JAM-A homophilic interaction during leukocyte transmigration.","date":"2009","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18849408","citation_count":53,"is_preprint":false},{"pmid":"24265754","id":"PMC_24265754","title":"Overexpression of JAM-A in non-small cell lung cancer correlates with tumor progression.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24265754","citation_count":51,"is_preprint":false},{"pmid":"17964041","id":"PMC_17964041","title":"Association of plasma levels of F11 receptor/junctional adhesion molecule-A (F11R/JAM-A) with human atherosclerosis.","date":"2007","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/17964041","citation_count":51,"is_preprint":false},{"pmid":"25070379","id":"PMC_25070379","title":"MicroRNA-495 induces breast cancer cell migration by targeting JAM-A.","date":"2014","source":"Protein & 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the interaction requires the membrane-proximal Ig-like domain 2 of JAM-A.\",\n      \"method\": \"Adhesion assays under static and physiological flow conditions, transfectant expression of JAM-A, domain deletion mutants\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (transfectants, flow assays, domain mutants), replicated in multiple cell types\",\n      \"pmids\": [\"11812992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human JAM-1 (F11R) localizes to cell-cell junctions via homophilic binding; recombinant JAM-1 expressed in CHO cells concentrates at contacts between two transfected cells (not between transfected and untransfected cells), and human platelets specifically bind JAM-1-expressing CHO cell monolayers.\",\n      \"method\": \"Immunofluorescence of CHO transfectants, platelet adhesion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization and adhesion assay, single lab, two orthogonal approaches\",\n      \"pmids\": [\"11171323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"F11R/JAM-A mediates adhesion of human platelets to cytokine-inflamed endothelial cells through homophilic interactions; the N-terminal region and the 1st Ig-fold of F11R are required, as shown by inhibition with recombinant soluble F11R and peptides spanning those domains.\",\n      \"method\": \"Platelet adhesion assays to immobilized recombinant sF11R and cytokine-stimulated HUVEC; inhibition with domain peptides\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal inhibition with soluble protein and domain-specific peptides, multiple readouts\",\n      \"pmids\": [\"12428104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Two regions of F11R (N-terminal S1–C23 and K70–C82 in the 1st Ig-fold) are critical for M.Ab.F11-induced platelet aggregation, secretion, potentiation, and adhesion; soluble recombinant F11R fully inhibits these responses.\",\n      \"method\": \"Platelet aggregation and adhesion assays with domain-specific peptides and recombinant sF11R; 3D structural modeling of active site\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — peptide mapping with functional assays plus structural modeling, multiple 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 signaling dissociates this complex, redistributes JAM-1 to the cell surface, and requires signaling through the JAM-1 cytoplasmic domain for MAP kinase activation and tube formation.\",\n      \"method\": \"Co-immunoprecipitation, JAM-1 cytoplasmic domain mutations, MAP kinase activation assays, endothelial tube formation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — co-IP plus mutagenesis plus functional angiogenesis assay in single study\",\n      \"pmids\": [\"12750158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"M.Ab.F11-mediated F11R signaling in platelets requires crosslinking of F11R with FcγRII, leading to actin filament assembly (PI3K-dependent, wortmannin-sensitive), increased intracellular calcium, phosphorylation of F11R (32 and 35 kDa forms), F11R dimerization, and association of F11R with integrin GPIIIa and CD9.\",\n      \"method\": \"Platelet activation assays, PI3K inhibition (wortmannin), co-immunoprecipitation of F11R with GPIIIa and CD9, calcium measurement, phosphorylation analysis\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods (co-IP, phosphorylation, Ca2+ measurement, inhibitor studies) in single study\",\n      \"pmids\": [\"15344881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAM-1 is recruited to cell-cell contacts in the mouse preimplantation embryo during the 8-cell stage (earlier than any other TJ protein analyzed), transiently localizes to the apical pole during compaction with PKCζ and PKCδ, and anti-JAM-1 neutralizing antibodies delay blastocoel cavity formation by impairing the TJ paracellular seal without affecting global embryo compaction.\",\n      \"method\": \"Immunofluorescence confocal microscopy of staged embryos, neutralizing antibody treatment with functional readout (blastocoel formation)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional antibody-blocking experiment in intact embryos\",\n      \"pmids\": [\"15494378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Endothelial-cell JAM-A (but not leukocyte JAM-A) mediates neutrophil transmigration in response to IL-1β and ischemia/reperfusion injury in vivo; JAM-A and PECAM-1 act sequentially (not additively) to mediate transmigration.\",\n      \"method\": \"Intravital microscopy in JAM-A KO and neutralizing antibody-treated mice; leukocyte transfer to JAM-A-deficient endothelium; dual JAM-A/PECAM-1 blockade\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus antibody blockade plus cell-transfer epistasis experiment in vivo\",\n      \"pmids\": [\"17505016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A is present in the plasma membrane of the head and flagellum of mouse spermatozoa; deletion of Jam-A causes flagellar ultrastructural defects, reduced progressive and hyperactivated motility before and after capacitation, and reduced litter size.\",\n      \"method\": \"Gene trap knockout, transmission electron microscopy, sperm motility analysis (CASA), immunofluorescence\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with ultrastructural and functional phenotypic readouts\",\n      \"pmids\": [\"18022613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A is a cell-surface marker exclusively on long-term repopulating hematopoietic stem cells (LTR-HSC); JAM-A+ cells sorted from whole bone marrow are highly enriched for LTR-HSC activity in transplantation assays.\",\n      \"method\": \"Flow cytometric sorting, colony-forming assays, competitive bone marrow transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional enrichment by transplantation, multiple hematopoietic tissues tested\",\n      \"pmids\": [\"17986666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JAM-A on neutrophils concentrates at the leading edge and uropod; a significant fraction is internalized into endosomal-like vesicles co-distributing with β1 integrin. In JAM-A-null neutrophils, β1 integrin internalization upon chemotactic stimuli is impaired, causing defective uropod retraction and reduced directional migration.\",\n      \"method\": \"Intravital microscopy, in vitro chemotaxis assays with JAM-A-null neutrophils, co-clustering experiments, BAPTA-AM integrin internalization inhibition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null plus pharmacological inhibition plus co-localization, in vivo and in vitro readouts\",\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 stabilizes the homophilic bond, and LFA-1 binding to domain 2 reduces homophilic bond strength to that of a domain-2 deletion mutant. The LFA-1/JAM-A heterophilic interaction is stronger than the JAM-A homophilic interaction.\",\n      \"method\": \"Atomic force microscopy adhesion measurements, competitive binding assays, domain deletion mutants of JAM-A\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biophysical force measurements with domain mutants, quantitative competition assays\",\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 transmigration through mouse cremasteric venules in a stimulus-dependent manner; when TNF-α directly stimulates neutrophils, these molecules are dispensable, but when neutrophil TNFR signaling is blocked, transmigration becomes dependent on all three endothelial molecules in sequence.\",\n      \"method\": \"Intravital microscopy, cell transfer with TNFR-KO leukocytes into ICAM-2/JAM-A/PECAM-1 KO recipient mice, site-of-arrest analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via genetic KO combinations and cell transfer, in vivo imaging\",\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 mice show enhanced β-catenin/TCF transcription and colonic crypt hyperproliferation reversible by Akt inhibition.\",\n      \"method\": \"JAM-A KO mice crossed to β-catenin/TCF reporter mice, Akt inhibitor rescue of hyperproliferation, in vitro dimerization-deficient mutant studies\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with pharmacological rescue, in vivo and in vitro validation of signaling pathway\",\n      \"pmids\": [\"21372850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"aPKC directly interacts with JAM-A in a PAR-3-independent manner and phosphorylates JAM-A at Ser285 upon recruitment to primordial junctions. S285-phosphorylated JAM-A localizes exclusively to tight junctions in polarized cells; S285 phosphorylation is required for functional epithelial barrier formation and single lumen specification in 3D culture. Protein phosphatase 2A dephosphorylates JAM-A at S285.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, non-phosphorylatable JAM-A/S285A mutant expression, 3D cyst culture, PP2A inhibition\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation assay with mutagenesis plus functional TJ and polarity readouts\",\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 enhanced platelet spreading and clot retraction (outside-in), but normal inside-out signaling (granule secretion, TxA2 generation, fibrinogen receptor activation), resulting in enhanced thrombotic function in vivo.\",\n      \"method\": \"Jam-A KO mice, platelet spreading and clot retraction assays (outside-in), granule secretion and aggregation assays (inside-out), intravital thrombosis models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic dissection of inside-out vs. outside-in signaling using multiple functional assays\",\n      \"pmids\": [\"22271446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"On the sperm flagellum, CASK interacts via its PDZ domain alternatively and non-synergistically with either JAM-A or PMCA4b. In the absence of JAM-A, CASK-PMCA4b interaction increases, inhibiting PMCA4b enzymatic activity, causing Ca2+ accumulation and reduced ATP, thus impairing motility. JAM-A positively regulates PMCA4b indirectly through CASK.\",\n      \"method\": \"Co-immunoprecipitation, PMCA4b enzymatic activity assay, Ca2+ and ATP measurements in Jam-A null sperm\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus enzymatic activity measurement plus ion/energy metabolite assays in genetic KO\",\n      \"pmids\": [\"22020416\"],\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 the small GTPase Rap2c to regulate epithelial barrier function. siRNA knockdown of each component phenocopies JAM-A loss (enhanced permeability). JAM-A also modulates RhoA activity and non-muscle myosin phosphorylation to control perijunctional actomyosin contraction.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of complex components, GTPase activity assays (Rap2c, RhoA), permeability assays, JAM-A KO mice\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, epistasis by siRNA, GTPase biochemistry, in vivo KO validation\",\n      \"pmids\": [\"23885123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Trans-dimerization of JAM-A (between adjacent cell surfaces) occurs at a distinct domain from cis-dimerization; residues 43NNP45 in the predicted trans-dimerization site are required. Trans- but not cis-null JAM-A mutants decrease Rap2 activity, and confluent cells (enabling trans-dimerization) show enhanced Rap2 activity, identifying trans-dimerization as a barrier-inducing molecular switch.\",\n      \"method\": \"Transfection of cis- and trans-null JAM-A alanine mutants, microsphere aggregation assays, atomic force microscopy, Rap2 GTPase activity assays, cell confluence experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — AFM force measurements, domain-specific mutagenesis, GTPase signaling assays, multiple orthogonal approaches\",\n      \"pmids\": [\"24672055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAM-A serves as a coreceptor for rotavirus entry into MA104 cells; the viral spike protein VP4 determines use of JAM-A as coreceptor, and JAM-A is required for infection by rotavirus strains RRV, Wa, and UK but not YM.\",\n      \"method\": \"Antibody blocking, RRV/YM reassortant virus analysis determining VP4 as the viral determinant, infection assays in MA104 cells\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic reassortant analysis plus antibody blocking identifies viral and host determinants\",\n      \"pmids\": [\"25481868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAM-A regulates planar orientation of the mitotic spindle in polarized epithelial cells by triggering transient Cdc42 and PI(3)K activation, generating a cortical PtdIns(3,4,5)P3 gradient and regulating cortical actin; in the absence of functional JAM-A, dynactin localization at the lateral cortex is reduced and the mitotic spindle is misaligned.\",\n      \"method\": \"JAM-A KO/functional mutant cells, live imaging of spindle orientation, PI(3)K and Cdc42 activity measurements, dynactin localization by immunofluorescence, 3D cyst morphogenesis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss of function with mechanistic signaling dissection (Cdc42, PI3K, PIP3 gradient) and direct dynactin localization\",\n      \"pmids\": [\"26306570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mechanical tension imposed on JAM-A activates RhoA via PI3K-dependent activation of GEF-H1 and p115 RhoGEF (further 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\": \"Magnetic bead tension assay on JAM-A, RhoA FRET biosensor, PI3K/FAK/ERK/Src kinase inhibitors, JAM-A Ser284 phospho-mutant expression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct mechanotransduction assay with pharmacological and mutagenesis dissection of pathway\",\n      \"pmids\": [\"26985018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"During intestinal inflammation, the Src kinase Yes-1 phosphorylates JAM-A at Y280 (cytoplasmic tail), reducing JAM-A association with active Rap2 and impairing barrier function; PTPN13 is the major phosphatase for p-JAM-A Y280. Src kinase inhibitor PP2 rescues cytokine-induced barrier defects. Y280 phosphorylation is increased in ulcerative colitis patient colonic epithelium.\",\n      \"method\": \"Phospho-specific antibodies, kinase/phosphatase siRNA knockdown, co-immunoprecipitation with Rap2, Src inhibitor rescue, human colitis tissue analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identified writer (Yes-1) and eraser (PTPN13) with functional rescue plus signaling link to Rap2, human tissue validation\",\n      \"pmids\": [\"30625033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity; simultaneous deletion of claudins and JAM-A causes loss of membrane appositions, macromolecule permeability barrier, and sporadic epithelial polarity defects, whereas deletion of either alone does not fully recapitulate these phenotypes.\",\n      \"method\": \"Systematic genome editing (CRISPR) of TJ components in epithelial cells; TJ strand ultrastructure, permeability assays, polarity markers\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — combinatorial CRISPR KO epistasis with functional barrier and polarity readouts\",\n      \"pmids\": [\"31467165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAM-A promotes claudin-5 expression via C/EBP-α transcription factor; JAM-A suppresses β-catenin transcriptional activity and activates EPAC, which increases C/EBP-α expression; C/EBP-α then directly binds the claudin-5 promoter to promote transcription, thereby reducing endothelial permeability.\",\n      \"method\": \"JAM-A KO mice (vascular permeability assays), C/EBP-α gain/loss-of-function, FITC-dextran permeability, β-catenin inhibition, EPAC activation, chromatin studies of claudin-5 promoter, human glioblastoma/ovarian cancer tissue analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus multiple gain/loss-of-function experiments establishing the full JAM-A→EPAC→C/EBP-α→claudin-5 pathway with direct promoter binding\",\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 (detected by a ZO-1 tension sensor), and increases traction forces at focal adhesions. p114RhoGEF is required for junctional actomyosin activity and TJ integrity on stiff but not soft ECM, placing JAM-A upstream of p114RhoGEF in mechanosensing.\",\n      \"method\": \"FRET-based ZO-1 tension sensor, traction force microscopy, JAM-A depletion, p114RhoGEF knockdown, variable stiffness ECM substrates\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct tension measurement with FRET sensor plus traction force microscopy and genetic epistasis\",\n      \"pmids\": [\"32697990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 cleaves JAM-A/F11R at the endothelial junction (at V232, identified by cleavage-resistant mutant JAM-AV232Y) in aged mice and cells exposed to reduced shear stress; loss of junctional JAM-A impairs endothelial wall shear stress mechanosensing, leading to inward hypertrophic arterial remodeling. Overexpression of ADAM17-cleavage-resistant JAM-AV232Y normalizes mechanosensing in aged resistance arteries.\",\n      \"method\": \"AAV9-mediated ADAM17 overexpression in young mice, JAM-A knockdown, cleavage-resistant JAM-AV232Y mutant rescue in vitro and in vivo, shear stress mechanosensing assays in aged mice\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identified ADAM17 as writer/sheddase with specific cleavage-resistant mutant rescue in vivo\",\n      \"pmids\": [\"34718985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A interacts with α3β1 integrin and tetraspanins CD151 and CD9 through its extracellular domain to regulate collective cell migration of polarized epithelial cells on laminin and collagen-I substrates; depletion of JAM-A reduces cryptic lamellipodia dynamics in the collective, while JAM-A depletion enhances motility of single cells.\",\n      \"method\": \"MDCK cell JAM-A/integrin/tetraspanin depletion, co-immunoprecipitation, domain mapping, live-cell migration assays, substrate specificity experiments\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with domain mapping plus functional migration assays with multiple KD conditions\",\n      \"pmids\": [\"35067832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A forms a multimolecular complex with tetraspanins CD9/CD81 and αvβ5 integrin; JAM-A binds Csk and inhibits αvβ5 integrin-associated Src activity. Loss of JAM-A increases Src downstream signaling (Erk1/2, Abi1, paxillin, Rac1 at cell contacts), increases cell-matrix turnover, and impairs contact inhibition of locomotion (CIL).\",\n      \"method\": \"Co-immunoprecipitation, Src/Erk/Rac1 activity assays, JAM-A KD with CIL functional assay, αvβ5 integrin engagement experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP establishing complex, kinase activity assays, genetic KD with defined CIL phenotype\",\n      \"pmids\": [\"35293964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A interacts with NF2 and LATS1 to function as an initiator of the Hippo signaling pathway; JAM-A dimerization is required since a dimerization-deficient mutant (JAM-A-DL1) fails to activate Hippo and phenocopies JAM-A deficiency. JAM-A loss or DL1 expression increases YAP activity and EVI1 transcription factor expression to drive intestinal epithelial proliferation.\",\n      \"method\": \"Co-immunoprecipitation (JAM-A with NF2/LATS1), YAP activity assays, dimerization-deficient mutant expression, siRNA knockdown, EVI1 expression analysis in JAM-A KO IEC\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifying pathway components, mutagenesis showing dimerization dependence, downstream signaling validation\",\n      \"pmids\": [\"35602956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In lymphatic endothelial cells, inflammatory cytokines induce formation of a ROCK2/JAM-A complex that tightens lymphatic cell-cell junctions and impedes lymphatic drainage; ROCK inhibition loosens lymphatic junctions. Lymphatic-specific ROCK2 knockout reversed lymphedema in mice in vivo.\",\n      \"method\": \"Microfluidic lymphatic-on-chip, co-immunoprecipitation of ROCK2 with JAM-A, ROCK isoform characterization, ROCK2 conditional KO mouse model with lymphedema readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifying ROCK2/JAM-A complex, in vitro chip model plus in vivo conditional KO rescue\",\n      \"pmids\": [\"37782785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"F11R mRNA levels are increased under hypoxia via ADAR1-mediated RNA editing of the 3'UTR; hyper-edited mature F11R mRNAs are retained in the nucleus via association with p54nrb, preventing cytoplasmic export and translation.\",\n      \"method\": \"RNA editing analysis under hypoxia, ADAR1/ADAR2 siRNA knockdown, nuclear/cytoplasmic fractionation, p54nrb RNA immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ADAR1 identified by knockdown, p54nrb interaction by RIP, fractionation showing nuclear retention; single lab\",\n      \"pmids\": [\"24147060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"F11R is expressed in smooth muscle cells of atherosclerotic arterial intima (not in normal media SMCs); cytokine stimulation induces F11R expression in cultured SMCs, and siRNA silencing of F11R blocks both migration and proliferation of inflamed SMCs.\",\n      \"method\": \"Immunofluorescence of human atherosclerotic arteries, RT-PCR and Western blot in cytokine-stimulated SMCs, siRNA knockdown with migration/proliferation assays\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined cellular phenotype in vitro, human tissue localization; single lab\",\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 TNF-α/IFN-γ via NF-κB and JAK/STAT pathways, is required for adhesion of human platelets to inflamed endothelium; siRNA silencing of F11R mRNA completely blocks cytokine-induced F11R protein upregulation and platelet adhesion.\",\n      \"method\": \"Transcription/translation inhibitors (actinomycin, parthenolide, AG-480), F11R siRNA knockdown in HUVEC, platelet adhesion assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — siRNA knockdown with functional platelet adhesion readout; pathway placement via signaling inhibitors; single lab\",\n      \"pmids\": [\"21703019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAM-A regulates permeability and inflammation in the intestinal epithelium; JAM-A-deficient mice show increased mucosal permeability (dextran flux, reduced TER) and altered expression of claudin-10 and claudin-15 in colonic mucosa. JAM-A loss also increases susceptibility to DSS-induced colitis with enhanced epithelial proliferation.\",\n      \"method\": \"JAM-A KO mice, dextran flux and TER measurements, immunoblot for claudins in KO vs. WT, JAM-A siRNA in epithelial monolayers, DSS colitis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple barrier readouts, claudin expression changes validated in vitro by siRNA, in vivo disease model\",\n      \"pmids\": [\"18039951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAM-A expression transcriptionally regulates HER2 by influencing binding of the transcription factor FOXA1 to a specific site in the HER2 gene promoter in breast cancer cells.\",\n      \"method\": \"JAM-A knockdown with FOXA1 ChIP at HER2 promoter, HER2 expression rescue experiments, promoter reporter assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at defined promoter region with genetic perturbation; single lab\",\n      \"pmids\": [\"35203384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nectin-3 (via its effector afadin) enables 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\": \"Co-expression of adhesion molecules in L fibroblasts lacking TJs/AJs, immunofluorescence co-localization, afadin requirement demonstrated\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reconstitution in fibroblast system with defined component requirements; single lab\",\n      \"pmids\": [\"18547333\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"F11R/JAM-A is a multifunctional immunoglobulin-superfamily transmembrane protein that (1) forms homophilic cis- and trans-dimers and heterophilic complexes with LFA-1, αvβ3, αIIbβ3, α3β1 integrin, αvβ5 integrin, tetraspanins CD9/CD81/CD151, and intracellular scaffolds ZO-2/afadin/PDZ-GEF1; (2) is phosphorylated at Ser285 by aPKC (promoting TJ maturation and dephosphorylated by PP2A) and at Tyr280 by Src kinase Yes-1 (impairing barrier via reduced Rap2 activity, reversed by PTPN13); (3) signals through Rap2c, RhoA (via GEF-H1/p115 RhoGEF in response to tension), Cdc42/PI(3)K (for planar spindle orientation), Akt/β-catenin (restraining proliferation), and the Hippo pathway (via NF2/LATS1/YAP to suppress proliferation); (4) regulates endothelial barrier by promoting C/EBP-α-driven claudin-5 transcription downstream of EPAC; (5) is shed by ADAM17 to generate soluble JAM-A that modulates thrombo-inflammation; and (6) acts as a receptor for reovirus entry (via VP4-dependent interaction) and as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling in platelets.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"F11R (JAM-A) is an immunoglobulin-superfamily transmembrane protein that functions as a central organizer of tight-junction assembly, epithelial and endothelial barrier integrity, leukocyte transmigration, and platelet-endothelial adhesion. It forms homophilic cis- and trans-dimers through distinct domains in its two extracellular Ig folds, with trans-dimerization acting as a molecular switch that activates Rap2c via a ZO-2/afadin/PDZ-GEF1 scaffold complex to promote barrier function; aPKC phosphorylation at Ser285 drives JAM-A to mature tight junctions, while Src-family kinase Yes-1 phosphorylation at Tyr280 disrupts Rap2 association and impairs the barrier [PMID:22371556, PMID:24672055, PMID:23885123, PMID:30625033]. JAM-A serves as a heterophilic ligand for LFA-1 (via its membrane-proximal Ig domain 2), enabling sequential ICAM-2/JAM-A/PECAM-1-dependent neutrophil diapedesis, and acts as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling in platelets and of αvβ5-associated Src activity via Csk recruitment in epithelial cells [PMID:11812992, PMID:19211506, PMID:22271446, PMID:35293964]. Beyond adhesion, JAM-A controls epithelial proliferation through dimerization-dependent activation of the Hippo pathway (NF2/LATS1/YAP) and suppression of Akt/β-catenin signaling, regulates planar spindle orientation via Cdc42/PI3K-generated PIP3 gradients, promotes claudin-5 transcription through an EPAC/C/EBP-α axis in endothelium, and transduces mechanical tension into RhoA activation via GEF-H1 and p115RhoGEF [PMID:35602956, PMID:21372850, PMID:26306570, PMID:32697990, PMID:32673519, PMID:26985018].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that F11R/JAM-A mediates cell-cell adhesion through homophilic binding answered the question of how this Ig-superfamily protein concentrates at intercellular junctions and supports platelet-endothelial contact.\",\n      \"evidence\": \"Immunofluorescence of CHO transfectants showing JAM-1 concentration only at transfected–transfected cell contacts; platelet adhesion assay\",\n      \"pmids\": [\"11171323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; no biophysical measurement of binding affinity\", \"Cis- vs. trans-dimerization not distinguished\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of JAM-A as a heterophilic ligand for LFA-1 (via Ig domain 2) and mapping of homophilic adhesion sites (N-terminal and first Ig fold) established the dual-mode adhesive logic underlying JAM-A's roles in leukocyte transmigration and platelet adhesion.\",\n      \"evidence\": \"Adhesion assays under flow with domain-deletion mutants (LFA-1); peptide/soluble-protein inhibition of platelet aggregation and adhesion to HUVEC\",\n      \"pmids\": [\"11812992\", \"12428104\", \"12008956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the JAM-A/LFA-1 interface\", \"Relative contribution of homophilic vs. heterophilic interactions during in vivo transmigration unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that JAM-A forms a complex with integrin αvβ3 in quiescent endothelium—dissociated by bFGF signaling to activate MAPK—established JAM-A as a signaling scaffold that couples junctional state to angiogenic responses.\",\n      \"evidence\": \"Co-immunoprecipitation, JAM-A cytoplasmic-domain mutants, MAP kinase assays, endothelial tube formation\",\n      \"pmids\": [\"12750158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between JAM-A and αvβ3 not mapped\", \"Downstream mechanism linking cytoplasmic domain to MAPK not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that JAM-A is the earliest tight-junction protein recruited to cell-cell contacts in the preimplantation embryo (8-cell stage), colocalizing with aPKC, and that its blockade delays blastocoel formation established a role in the very first polarization and sealing event in mammalian development.\",\n      \"evidence\": \"Confocal immunofluorescence of staged mouse embryos; neutralizing-antibody functional assay\",\n      \"pmids\": [\"15494378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of early recruitment (before other TJ proteins) not elucidated\", \"aPKC-JAM-A phosphorylation relationship not yet tested at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo knockout and antibody-blockade studies resolved that endothelial (not leukocyte) JAM-A is the critical partner for neutrophil transmigration and acts sequentially with PECAM-1 and ICAM-2, while intestinal JAM-A loss increases mucosal permeability and susceptibility to colitis.\",\n      \"evidence\": \"Intravital microscopy in JAM-A KO mice with leukocyte transfer; DSS colitis model; barrier assays in KO intestine\",\n      \"pmids\": [\"17505016\", \"19211506\", \"18039951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal from endothelial JAM-A that initiates the transmigration step not identified\", \"Whether barrier defects are cell-autonomous vs. secondary to altered claudin expression not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"JAM-A KO spermatozoa display flagellar ultrastructural defects and reduced motility, revealing an unexpected role for JAM-A outside classical junctional contexts; JAM-A also marked long-term repopulating hematopoietic stem cells, broadening its functional territory.\",\n      \"evidence\": \"Gene-trap KO with TEM and CASA sperm motility analysis; competitive bone-marrow transplantation of JAM-A+ sorted cells\",\n      \"pmids\": [\"18022613\", \"17986666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking JAM-A to flagellar structure unknown at this point\", \"Functional role of JAM-A on HSCs (beyond marker) not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Biophysical AFM measurements showed that LFA-1 binding to JAM-A domain 2 destabilizes JAM-A homophilic bonds, providing the force-based mechanism by which leukocytes open junctions; concurrently, JAM-A was shown to regulate β1-integrin internalization in neutrophils, linking it to directional migration.\",\n      \"evidence\": \"Atomic force microscopy with domain mutants; intravital microscopy and chemotaxis assays with JAM-A-null neutrophils\",\n      \"pmids\": [\"18849408\", \"19118219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LFA-1-induced destabilization not resolved at atomic level\", \"Whether integrin internalization role generalizes beyond neutrophils untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"JAM-A was shown to restrain intestinal epithelial proliferation through dimerization-dependent suppression of Akt/β-catenin signaling, directly linking junctional adhesion to growth control.\",\n      \"evidence\": \"JAM-A KO mice crossed to β-catenin/TCF reporter; Akt inhibitor rescue of crypt hyperproliferation; dimerization-deficient mutants in vitro\",\n      \"pmids\": [\"21372850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JAM-A dimerization biochemically inhibits Akt not defined\", \"Whether proliferation effect is Hippo-independent or feeds through it\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"aPKC was identified as the kinase phosphorylating JAM-A at Ser285 (dephosphorylated by PP2A), directing JAM-A to tight junctions and controlling single-lumen specification; separately, JAM-A was established as an endogenous inhibitor of integrin αIIbβ3 outside-in signaling in platelets, and CASK was found to link JAM-A to PMCA4b regulation of flagellar Ca²⁺.\",\n      \"evidence\": \"In vitro kinase assays, S285A mutants in 3D cysts; Jam-A KO platelet spreading/clot retraction vs. inside-out assays; co-IP/PMCA4b activity in KO sperm\",\n      \"pmids\": [\"22371556\", \"22271446\", \"22020416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"aPKC recruitment mechanism to JAM-A (PAR-3-independent) not structurally explained\", \"How JAM-A inhibits outside-in signaling at the molecular level unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of the ZO-2/afadin/PDZ-GEF1 scaffold and Rap2c as the GTPase downstream of JAM-A provided the first complete signaling module linking JAM-A to barrier regulation, complemented by RhoA/actomyosin control.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA epistasis of each scaffold component, Rap2c and RhoA GTPase activity assays, JAM-A KO mice barrier measurements\",\n      \"pmids\": [\"23885123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the scaffold unknown\", \"Whether Rap2c and RhoA arms are independent or cross-regulated not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Dissection of cis- versus trans-dimerization interfaces showed that trans-dimerization (residues 43NNP45) specifically activates Rap2 and induces barrier, establishing trans-dimerization as the contact-dependent molecular switch.\",\n      \"evidence\": \"Alanine scanning of cis/trans interfaces, AFM, microsphere aggregation, Rap2 GTPase assays in confluent vs. subconfluent cells\",\n      \"pmids\": [\"24672055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of mammalian JAM-A trans-dimer confirming mutagenesis findings\", \"Whether cis-dimerization has separable signaling outputs remains unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"JAM-A was found to orient the mitotic spindle in polarized epithelia via transient Cdc42/PI3K activation and cortical PIP3 gradient generation, linking junctional adhesion to tissue architecture maintenance during cell division.\",\n      \"evidence\": \"JAM-A KO/functional mutant live imaging of spindle, PI3K/Cdc42 activity measurements, dynactin localization, 3D cyst morphogenesis\",\n      \"pmids\": [\"26306570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JAM-A activates Cdc42 transiently and locally not molecularly defined\", \"Whether spindle orientation defect contributes to tumorigenesis not tested in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Direct mechanical tension on JAM-A was shown to activate RhoA through PI3K-dependent GEF-H1 and p115RhoGEF (requiring Ser284 phosphorylation), establishing JAM-A as a junctional mechanosensor.\",\n      \"evidence\": \"Magnetic bead tension assay, RhoA FRET biosensor, kinase inhibitors, Ser284 phospho-mutant\",\n      \"pmids\": [\"26985018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase for Ser284 in the mechanosensing context not determined\", \"Whether mechanotransduction feeds back to Rap2 signaling unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Src-family kinase Yes-1 was identified as the writer and PTPN13 as the eraser for JAM-A Tyr280 phosphorylation, which impairs Rap2 association and barrier function during inflammation—directly linking cytokine signaling to the JAM-A/Rap2 switch in ulcerative colitis tissue.\",\n      \"evidence\": \"Phospho-specific antibodies, siRNA of Yes-1/PTPN13, co-IP with Rap2, Src inhibitor rescue, human colitis tissue\",\n      \"pmids\": [\"30625033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how Y280 phosphorylation disrupts Rap2 binding unknown\", \"Whether Y280 and S285 phosphorylation events are coordinated or independent not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two parallel downstream pathways of JAM-A were elaborated: (1) an EPAC/C/EBP-α axis that transcriptionally activates claudin-5 in endothelium, and (2) a mechanosensitive role upstream of p114RhoGEF/ZO-1 tension regulation that depends on substrate stiffness.\",\n      \"evidence\": \"JAM-A KO mice with vascular permeability assays, C/EBP-α gain/loss-of-function, ChIP on claudin-5 promoter; FRET ZO-1 tension sensor, traction force microscopy on variable-stiffness substrates\",\n      \"pmids\": [\"32673519\", \"32697990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EPAC/C/EBP-α pathway operates in epithelia beyond endothelium untested\", \"How JAM-A depletion triggers p114RhoGEF recruitment molecularly unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ADAM17 was identified as the sheddase cleaving JAM-A at V232 in aged endothelium under low shear stress, with loss of junctional JAM-A impairing mechanosensing and causing inward arterial remodeling—linking JAM-A shedding to vascular aging.\",\n      \"evidence\": \"AAV9-ADAM17 overexpression in young mice, cleavage-resistant JAM-AV232Y mutant rescue in vivo, shear stress assays in aged arteries\",\n      \"pmids\": [\"34718985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether soluble cleaved JAM-A ectodomain has signaling activity not addressed\", \"Other sheddases that may contribute in non-endothelial contexts unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"JAM-A was placed at the apex of Hippo signaling (via NF2/LATS1 interaction requiring dimerization) and as a Csk-recruiting inhibitor of αvβ5/Src signaling for contact inhibition of locomotion, while its extracellular domain was found to complex with α3β1 integrin and tetraspanins CD9/CD81/CD151 to regulate collective migration.\",\n      \"evidence\": \"Co-IP of JAM-A with NF2/LATS1, dimerization-deficient mutant phenocopy, YAP/EVI1 readouts; co-IP with Csk and αvβ5, Src/Erk/Rac1 activity in KD; co-IP with α3β1/CD151/CD9 and substrate-specific migration assays\",\n      \"pmids\": [\"35602956\", \"35293964\", \"35067832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Hippo and Akt/β-catenin pathways are redundant or additive in proliferation control unresolved\", \"Structural basis of JAM-A–tetraspanin interaction not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ROCK2 was identified as a JAM-A partner in lymphatic endothelium where inflammation-induced ROCK2/JAM-A complex formation tightens junctions and impedes drainage, revealing a tissue-specific junctional-tightening mechanism distinct from the canonical barrier role.\",\n      \"evidence\": \"Co-IP of ROCK2 with JAM-A, microfluidic lymphatic chip, lymphatic-specific ROCK2 conditional KO reversing lymphedema in vivo\",\n      \"pmids\": [\"37782785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ROCK2 directly phosphorylates JAM-A in this context not tested\", \"Generalizability to human lymphedema not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how the multiple phosphorylation events on JAM-A (Ser285, Tyr280, Ser284) are temporally coordinated during junction maturation and inflammation; the high-resolution structural basis of the JAM-A trans-dimer and its heterophilic complexes with integrins, tetraspanins, and Hippo components; whether JAM-A's anti-proliferative functions (Hippo vs. Akt/β-catenin) are synergistic or pathway-specific; and the in vivo significance of soluble JAM-A ectodomain generated by ADAM17 shedding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated phospho-signaling model across Ser285/Tyr280/Ser284\", \"No atomic-resolution structures of JAM-A heterophilic complexes\", \"Functional significance of shed soluble JAM-A in vivo remains untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 3, 11, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [17, 28, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 28]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 6, 8, 14]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [8, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 10, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [14, 17, 18, 23, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 20, 21, 22, 29]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3, 5, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 34]}\n    ],\n    \"complexes\": [\n      \"ZO-2/afadin/PDZ-GEF1 scaffold\",\n      \"CD9/CD81/CD151 tetraspanin web\",\n      \"NF2/LATS1 Hippo complex\",\n      \"ROCK2/JAM-A lymphatic complex\"\n    ],\n    \"partners\": [\n      \"ITGAL\",\n      \"ITGB3\",\n      \"ITGA3\",\n      \"CD9\",\n      \"TJP2\",\n      \"CASK\",\n      \"NF2\",\n      \"LATS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}