{"gene":"JAM2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2000,"finding":"JAM-2 localizes to tight junctional complexes of polarized cells and newly formed cell-cell contacts within minutes, and its expression reduces paracellular permeability of cell monolayers, indicating a role in interendothelial junctional complex sealing.","method":"Real-time video microscopy, transfection of JAM-2 cDNA into cell monolayers with permeability assays, immunolocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment tied to functional consequence (permeability), single lab, two orthogonal methods","pmids":["11053409"],"is_preprint":false},{"year":2001,"finding":"JAM3 is the heterotypic counter-receptor for JAM2; JAM3 ectodomain binds firmly to JAM2-Fc, and JAM3 expressed on T cells mediates JAM2 adhesion, identifying JAM3 as the 43-kDa counter-receptor on lymphocytes.","method":"Fc-fusion pulldown (JAM2-Fc capturing JAM3), static adhesion assays with JAM3-expressing cells, polyclonal anti-JAM3 serum blocking experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding assays with Fc fusions, cell adhesion assays, and antibody blocking; independently corroborated by multiple subsequent studies","pmids":["11590146"],"is_preprint":false},{"year":2002,"finding":"JAM2 interacts with α4β1 integrin on T cells, but this interaction requires prior heterotypic engagement of JAM2 with JAM3; the first Ig-like fold of JAM2 is sufficient for binding both JAM3 and α4β1, and Asp-82 in the C-D loop is not required for α4β1 binding.","method":"Neutralizing integrin antibodies, small-molecule integrin inhibitor (TBC 772), JAM3 blocking serum, JAM2 domain/point mutants in adhesion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal inhibition approaches plus domain mutagenesis identifying the binding fold and ruling out a specific residue","pmids":["12070135"],"is_preprint":false},{"year":2002,"finding":"VE-JAM/JAM2 mediates adhesion to T cells, NK cells, and dendritic cells through heterotypic interaction with JAM3 expressed on those immune cells.","method":"Cell adhesion assays, antibody blocking, JAM3 cloning and functional characterization","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell adhesion functional assays with receptor identification, single lab, consistent with concurrent reports","pmids":["11823489"],"is_preprint":false},{"year":2003,"finding":"JAM-2 directly associates with the cell polarity protein PAR-3 via the first PDZ domain of PAR-3; JAM-2 also associates with ZO-1 in a PDZ domain-dependent manner. Junctional clustering of JAM-2 (regulated by serine phosphorylation) recruits endogenous PAR-3 and ZO-1 to cell-cell contacts in CHO cells.","method":"Co-immunoprecipitation, ectopic expression of JAM-2 in CHO cells, immunofluorescence localization, PDZ domain deletion mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-deletion mapping, and functional localization experiments in ectopic expression system; independently consistent with JAM-1/PAR-3 work from same group","pmids":["12953056"],"is_preprint":false},{"year":2005,"finding":"JAM-B (JAM2) and JAM-C undergo heterophilic interaction at cell-cell contacts; JAM-B recruits and stabilizes JAM-C in junctional complexes. Soluble JAM-B dissociates JAM-C homodimers to form JAM-B/JAM-C heterodimers, indicating higher affinity of JAM-C for JAM-B than for itself. Disrupting JAM-B/JAM-C heterodimers with anti-JAM-C antibodies liberates JAM-C to the apical surface, enabling interaction with the leukocyte counter-receptor αMβ2 integrin.","method":"Cell-cell contact co-localization, soluble protein competition assays, antibody-mediated complex disruption, αMβ2-dependent leukocyte adhesion assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding competition, antibody disruption, functional adhesion readout) establishing a mechanistic regulatory model","pmids":["16093349"],"is_preprint":false},{"year":2005,"finding":"In vivo blockade of JAM-B (using neutralizing antibodies) reduces leukocyte extravasation into the skin and attenuates allergic contact dermatitis; combined JAM-B and JAM-C blockade produces additive inhibition, indicating distinct functions for each molecule in cutaneous inflammation.","method":"In vivo antibody blockade in murine allergic contact dermatitis model, histology, enzyme activity assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional blockade with defined cellular phenotype (leukocyte infiltration), single lab","pmids":["16297198"],"is_preprint":false},{"year":2006,"finding":"Jam-B (JAM2) is specifically expressed in undifferentiated embryonic stem cells, but Jam-B knockout mice are fertile with no overt developmental defects, and neural and hematopoietic stem cells from knockout mice show normal self-renewal and differentiation, demonstrating JAM-B is dispensable for stem cell identity.","method":"DNA microarray expression profiling, Jam-B homozygous knockout mouse generation, stem cell self-renewal and differentiation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple stem cell lineage readouts; negative result is mechanistically informative and robustly established","pmids":["16914739"],"is_preprint":false},{"year":2009,"finding":"JAM-B supports lymphocyte rolling and firm adhesion through interaction with α4β1 (VLA-4) integrin; blocking JAM-B in vivo reduces rolling interactions in skin microvasculature and impairs sensitization phase of contact hypersensitivity.","method":"Intravital microscopy, dynamic flow chamber T-lymphocyte perfusion over JAM-B-coated slides, integrin-blocking antibodies, adoptive transfer experiments","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including in vitro flow chamber, integrin blocking, and in vivo intravital microscopy with functional immune readout","pmids":["19740376"],"is_preprint":false},{"year":2011,"finding":"Zebrafish jamb and jamc are essential for myocyte fusion to form syncytial muscle fibres; the encoded receptors physically interact and must engage in trans between neighbouring cells for fusion to occur. Loss of either gene results in mononuclear fast-twitch muscle fibres without other overt defects.","method":"Heritable zebrafish mutations, in vivo muscle development analysis, cell transplantation (trans interaction requirement), dynamic co-expression analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function with specific cellular phenotype, trans-interaction requirement established by transplantation, physical interaction confirmed","pmids":["22180726"],"is_preprint":false},{"year":2014,"finding":"Jam-B/Jam-C interaction between hematopoietic stem/progenitor cells (HSPC) and bone marrow stromal cells is required for HSPC homing and reconstitution; blocking Jam-C with a monoclonal antibody inhibits reconstitution and progenitor homing in a Jam-B-dependent manner and induces HSPC mobilization. The functional adhesive interaction between JAM-B and JAM-C exists between human HSPC and mesenchymal stem cells but not endothelial cells or osteoblasts.","method":"Blocking monoclonal antibody against Jam-C, bone marrow reconstitution assays after irradiation, HSPC mobilization measurements, adhesion assays between human cell types","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking antibody with defined cellular phenotype (homing, reconstitution), JAM-B dependence demonstrated, single lab","pmids":["24357068"],"is_preprint":false},{"year":2015,"finding":"TGF-β3 suppresses JAM-B expression via two mechanisms: (1) post-translational degradation through the ubiquitin-proteasome pathway requiring Smad signaling, and (2) mRNA destabilization requiring ERK1/2 and p54 JNK activation. Blockade of the ubiquitin-proteasome pathway abrogates TGF-β3-induced loss of JAM-B at cell-cell interfaces in Sertoli cells.","method":"Pharmacological inhibitors, siRNA knockdown of Smad and kinases, co-immunoprecipitation, mRNA stability assay, immunofluorescence staining","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mRNA stability assay, proteasome inhibition, siRNA, Co-IP) establishing two distinct regulatory mechanisms","pmids":["25817991"],"is_preprint":false},{"year":2016,"finding":"JAM-2 is expressed somatodendritically in neurons and acts as an inhibitory myelin-guidance molecule that prevents oligodendrocyte myelination of the somatodendritic compartment; disruption of dynamic neuron-oligodendrocyte signaling leads to aberrant myelination of somata and dendrites.","method":"Purified spinal cord neuron-oligodendrocyte myelinating co-culture, chemical cross-linking, next-generation sequencing, candidate profiling","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-culture system with defined myelination phenotype, candidate identification by sequencing; single lab","pmids":["27499083"],"is_preprint":false},{"year":2016,"finding":"PRL-3 (PTP4A3) physically interacts with JAM2 in colon cancer cells, as shown by co-immunoprecipitation and immunofluorescence; PRL-3 expression affects cell motility, spreading speed, and cell-matrix adhesion.","method":"Co-immunoprecipitation, immunofluorescence, cell wounding assay, cell spread assay, cell-matrix adhesion assay","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying interaction, functional assays present but pathway placement is incomplete, single lab","pmids":["27588115"],"is_preprint":false},{"year":2016,"finding":"During hepatic fibrogenesis, JAM-C is de novo expressed on myofibroblastic hepatic stellate cells, linking them as pericytes to JAM-B-positive endothelial cells; soluble JAM-C blocks stellate cell contractility, increases motility, and reduces endothelial tubulogenesis and endothelial-stellate cell interaction, indicating JAM-B/JAM-C interaction stabilizes vessel walls.","method":"Immunohistochemistry, flow cytometry, contractility and migration assays, endothelial tubulogenesis assay, soluble JAM-C treatment","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with soluble protein disruption, cell-type-specific expression localization, single lab","pmids":["27111582"],"is_preprint":false},{"year":2018,"finding":"JAM-B deficiency in mice (JAM-B−/−) ameliorates autoimmune-mediated liver fibrosis in a model of autoimmune hepatitis, and soluble recombinant JAM-C also reduces fibrosis; this effect is independent of leukocyte infiltration, suggesting JAM-B/JAM-C interactions directly contribute to fibrotic remodeling rather than through leukocyte recruitment.","method":"JAM-B knockout mice, autoimmune hepatitis mouse model, soluble recombinant JAM-C treatment, histological quantification of fibrosis and leukocyte infiltration","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined phenotype and orthogonal soluble protein intervention; single lab","pmids":["29753567"],"is_preprint":false},{"year":2018,"finding":"In JAM-B−/− mice subjected to EAE, inflammatory cells accumulate in leptomeningeal and perivascular spaces but fail to enter the CNS parenchyma, ameliorating EAE. JAM-B is not required for CD4+ T-cell arrest or extravasation across the BBB endothelium, but its absence traps cells at CNS border zones, indicating JAM-B facilitates parenchymal entry rather than initial BBB crossing.","method":"JAM-B knockout mice, EAE induction with MOG peptide, adoptive transfer of CD4+ T cells, immunofluorescence, flow cytometry of CNS infiltrating cells","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with specific cellular phenotype and mechanistic distinction (parenchymal entry vs BBB crossing), single lab","pmids":["29920328"],"is_preprint":false},{"year":2020,"finding":"Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification (PFBC); truncating mutations (p.L48*, p.M1?) abolish protein expression, and the p.W168C missense mutation prevents JAM2 protein translocation to the plasma membrane, implicating JAM2 in neurovascular unit integrity.","method":"Whole genome sequencing, homozygosity mapping, Western blot of mutant proteins in transfected CHO cells, immunofluorescence of mutant protein localization","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics linked to cellular mechanism (loss of membrane localization for missense mutant, loss of protein for truncating mutants), replicated across multiple unrelated families and independently confirmed in a separate study","pmids":["31851307"],"is_preprint":false},{"year":2020,"finding":"Biallelic JAM2 variants cause loss of JAM2 mRNA expression and absence of JAM2 protein in patient fibroblasts (loss-of-function mechanism); the jam2 complete knockout mouse recapitulates the human PFBC phenotype with vacuolation, reactive astrogliosis, and neuronal density reduction, establishing JAM2 as a blood-brain barrier tight-junction protein required for CNS homeostasis.","method":"Exome sequencing with homozygosity mapping, patient fibroblast mRNA and protein expression analysis, jam2 KO mouse neuropathology","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived cell mechanistic validation plus in vivo KO mouse phenotypic confirmation; independently replicates findings of concurrent study (PMID 31851307)","pmids":["32142645"],"is_preprint":false},{"year":2020,"finding":"JAM-B silencing in pancreatic cancer cells reduces cell migration and invasion, and decreases expression of c-Src and MMP9, placing JAM-B upstream of the c-Src/MMP9 signaling pathway in pancreatic cancer invasion.","method":"shRNA-mediated JAM-B silencing, scratch wound assays, Transwell invasion assays, subcutaneous xenograft mouse model, immunohistochemistry for c-Src and MMP9","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with phenotypic readout and pathway markers but no direct mechanistic linkage established","pmids":["32231730"],"is_preprint":false},{"year":2022,"finding":"Lactobacillus johnsonii GAPDH (moonlighting surface protein) physically binds JAM-2 on mouse gut epithelial cells; this interaction is associated with repair of damaged tight junctions and upregulation of tight junction genes in Caco-2 cells.","method":"Affinity resin pulldown of gut surface proteins, protein identification by mass spectrometry, Caco-2 cell barrier repair assay, RNA sequencing","journal":"Food & function","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single affinity pulldown identifying the interaction; functional consequence shown indirectly, single lab","pmids":["36069670"],"is_preprint":false},{"year":2022,"finding":"In leukocytes, JAM-B protein localizes to the cytoplasm, Golgi apparatus, and nucleus (around ring-shaped structures); nuclear localization occurs via the classical importin-α/β pathway mediated through JAM-B nuclear localization and export signals. Under inflammatory stimuli, JAM-B transcription is regulated via NF-κB-dependent pathways, and at the post-translational level JAM-B is regulated by ubiquitin-proteasome pathways involving APC/C (ubiquitination) and HAUSP/USP7 (de-ubiquitination).","method":"Immunoassays, qPCR, pharmacological inhibitors of importin pathway and NF-κB signaling, proteasome inhibitors","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor-based pathway assignment, single lab, no direct mutagenesis of NLS/NES signals or ubiquitin site mapping","pmids":["35955781"],"is_preprint":false},{"year":2023,"finding":"A Pou4f1-Tbr1-Jam2 transcriptional hierarchy controls formation of JAM2-expressing orientation-selective retinal ganglion cells (J-RGCs); Pou4f1 directly binds regulatory elements of both Tbr1 and Jam2 (identified by CUT&Tag), and Pou4f1 is required for expression of Tbr1 and Jam2 in J-RGCs.","method":"CUT&Tag chromatin profiling of Pou4f1 binding sites, genetic loss-of-function (Pou4f1 knockout), reporter gene assays for enhancer activity","journal":"Frontiers in ophthalmology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag plus KO plus reporter assay establishing direct upstream transcriptional regulation; single lab","pmids":["38469155"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, Jam2b (ortholog of human JAM2) functions downstream of the transcription factor Hand2 and is required for emergence of secondary vascular field (SVF) endothelial progenitors that give rise to intestinal vasculature; double maternal-zygotic jam2a;jam2b mutants show greatly reduced SVF cells and defective intestinal vasculature. Hand2 is required to induce Jam2b expression and the downstream vasculogenic transcription factor Etv2/Etsrp.","method":"Time-lapse imaging, jam2b:Cre lineage tracing, double maternal-zygotic jam2a;jam2b mutant zebrafish, hand2 loss-of-function, etv2 expression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with lineage tracing and time-lapse; preprint, not yet peer-reviewed","pmids":["41278682"],"is_preprint":true}],"current_model":"JAM2 (JAM-B) is a transmembrane immunoglobulin superfamily adhesion molecule that forms heterodimeric complexes with JAM3 (JAM-C) via its first Ig-like fold, recruits polarity proteins PAR-3 and ZO-1 through PDZ domain interactions (regulated by serine phosphorylation), engages α4β1 integrin on leukocytes (facilitated by prior JAM3 binding), acts as an inhibitory somatodendritic cue preventing aberrant oligodendrocyte myelination, is essential for vertebrate myocyte fusion (acting in trans with JAM-C), contributes to neurovascular unit integrity and blood-brain barrier paracellular function (biallelic loss causes primary familial brain calcification), and its expression is regulated post-translationally by TGF-β3 via Smad-dependent ubiquitin-proteasome degradation and ERK/JNK-mediated mRNA destabilization."},"narrative":{"mechanistic_narrative":"JAM2 (JAM-B) is a tight-junction-associated immunoglobulin-superfamily adhesion molecule that seals interendothelial/interepithelial junctions and couples cell-cell adhesion to leukocyte trafficking, myogenesis, and neurovascular integrity [PMID:11053409, PMID:11590146]. Its principal binding partner is JAM3 (JAM-C): the JAM-B ectodomain forms high-affinity heterodimers that recruit and stabilize JAM-C in junctional complexes, and JAM-B's first Ig-like fold mediates both this heterotypic interaction and a JAM3-dependent engagement of α4β1 (VLA-4) integrin on lymphocytes [PMID:11590146, PMID:12070135, PMID:16093349]. Through serine-phosphorylation-regulated junctional clustering, JAM-2 binds the polarity protein PAR-3 and ZO-1 via PDZ-domain interactions, recruiting them to nascent cell-cell contacts [PMID:12953056]. Functionally, JAM-B supports lymphocyte rolling and firm adhesion and promotes leukocyte entry into tissue and the CNS parenchyma without being required for the initial BBB crossing [PMID:19740376, PMID:29920328], and acts in trans with JAM-C to drive myocyte fusion into syncytial muscle fibres [PMID:22180726]. In the nervous system JAM-2 is a somatodendritic inhibitory cue that prevents oligodendrocyte myelination of neuronal somata and dendrites [PMID:27499083]. Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification, with truncating alleles abolishing protein and a missense allele (p.W168C) blocking trafficking to the plasma membrane, and the knockout mouse recapitulates the neuropathology, establishing JAM2 as a blood-brain-barrier tight-junction protein required for CNS homeostasis [PMID:31851307, PMID:32142645]. JAM-B expression is post-translationally suppressed by TGF-β3 through Smad-dependent ubiquitin-proteasome degradation and ERK/JNK-mediated mRNA destabilization [PMID:25817991].","teleology":[{"year":2000,"claim":"Established that JAM-2 is a junctional component whose expression actively seals paracellular barriers, defining its baseline role in tight-junction integrity.","evidence":"Real-time video microscopy and permeability assays in JAM-2-transfected monolayers","pmids":["11053409"],"confidence":"Medium","gaps":["Did not identify binding partners mediating the sealing","No in vivo barrier validation"]},{"year":2001,"claim":"Identified JAM3 as the heterotypic counter-receptor for JAM2, answering what molecule JAM2 engages on apposed cells and lymphocytes.","evidence":"JAM2-Fc pulldown, static adhesion assays with JAM3-expressing T cells, antibody blocking","pmids":["11590146"],"confidence":"High","gaps":["Affinity and stoichiometry of the heterodimer not quantified","Structural basis of binding not resolved"]},{"year":2002,"claim":"Showed JAM2 additionally engages α4β1 integrin on leukocytes but only after prior JAM3 binding, and mapped both interactions to the first Ig-like fold, linking adhesion architecture to leukocyte recruitment.","evidence":"Integrin-blocking antibodies, small-molecule inhibitor, JAM3 blocking serum, and JAM2 domain/point mutants in adhesion assays; concurrent immune-cell adhesion characterization","pmids":["12070135","11823489"],"confidence":"High","gaps":["Conformational change converting JAM2 to an integrin ligand not defined","In vivo relevance of integrin engagement not yet tested in this work"]},{"year":2003,"claim":"Connected JAM2 adhesion to intracellular polarity machinery by demonstrating phosphorylation-regulated, PDZ-dependent recruitment of PAR-3 and ZO-1, explaining how junctional JAM2 organizes the contact site.","evidence":"Co-immunoprecipitation, PDZ-domain deletion mutants, and immunofluorescence in CHO cells ectopically expressing JAM-2","pmids":["12953056"],"confidence":"High","gaps":["Kinase controlling the regulatory serine phosphorylation not identified","Done in ectopic CHO system, not native junctions"]},{"year":2005,"claim":"Defined the regulatory logic of the JAM-B/JAM-C heterodimer—JAM-B sequesters JAM-C, and disrupting the pair liberates JAM-C to engage αMβ2 integrin—establishing JAM-B as a gatekeeper of leukocyte adhesion; in vivo blockade reduced leukocyte extravasation in skin.","evidence":"Soluble protein competition, antibody-mediated complex disruption, αMβ2 adhesion assays; murine allergic contact dermatitis blockade","pmids":["16093349","16297198"],"confidence":"High","gaps":["Trigger for physiological heterodimer disruption in vivo unknown","Quantitative affinity differences inferred from competition, not direct binding constants"]},{"year":2006,"claim":"Tested whether the embryonic-stem-cell-enriched JAM-B is required for stemness, finding it dispensable for stem cell self-renewal and differentiation, narrowing its functional scope.","evidence":"Jam-B knockout mice with neural and hematopoietic stem cell self-renewal/differentiation assays","pmids":["16914739"],"confidence":"High","gaps":["Does not address adhesion functions of JAM-B in other tissues","Possible redundancy with related JAMs not examined"]},{"year":2009,"claim":"Resolved the dynamic step of leukocyte trafficking that JAM-B controls, showing it supports both rolling and firm adhesion via α4β1 in skin microvasculature and is required for contact-hypersensitivity sensitization.","evidence":"Intravital microscopy, flow-chamber lymphocyte perfusion over JAM-B, integrin blockade, adoptive transfer","pmids":["19740376"],"confidence":"High","gaps":["Relative contribution of JAM3 versus integrin engagement in vivo not separated","Endothelial signaling downstream of JAM-B engagement unknown"]},{"year":2011,"claim":"Revealed a developmental, non-immune role: JAM-B and JAM-C must interact in trans between adjacent myoblasts to drive myocyte fusion, defining a requirement for syncytial muscle formation.","evidence":"Heritable zebrafish jamb/jamc mutants, cell transplantation establishing trans requirement, physical interaction analysis","pmids":["22180726"],"confidence":"High","gaps":["Fusogenic machinery downstream of JAM engagement not identified","Conservation of myocyte-fusion role in mammals not addressed here"]},{"year":2014,"claim":"Extended JAM-B/JAM-C adhesion to the bone marrow niche, showing the interaction between HSPCs and stromal/mesenchymal cells is required for homing and reconstitution.","evidence":"Anti-Jam-C blocking antibody, bone marrow reconstitution and homing assays, human cell-type adhesion comparisons","pmids":["24357068"],"confidence":"Medium","gaps":["JAM-B-side signaling in HSPCs not dissected","Single lab, blocking-antibody-based"]},{"year":2015,"claim":"Defined how JAM-B levels are controlled, showing TGF-β3 suppresses JAM-B by two parallel routes—Smad-dependent ubiquitin-proteasome degradation and ERK/JNK-driven mRNA destabilization.","evidence":"Pharmacological inhibitors, siRNA against Smad and kinases, Co-IP, mRNA stability assays in Sertoli cells","pmids":["25817991"],"confidence":"High","gaps":["E3 ligase mediating degradation not identified","Generality beyond Sertoli cells not established"]},{"year":2016,"claim":"Identified JAM-2 as a somatodendritic inhibitory myelin-guidance cue, answering how neurons restrict oligodendrocyte myelination to axons.","evidence":"Neuron-oligodendrocyte myelinating co-culture, chemical cross-linking, candidate sequencing","pmids":["27499083"],"confidence":"Medium","gaps":["Oligodendrocyte-side receptor not defined in this work","Downstream inhibitory signaling pathway unknown"]},{"year":2016,"claim":"Implicated JAM-B/JAM-C adhesion in vascular wall stabilization during fibrogenesis, linking JAM-B-positive endothelium to JAM-C-expressing pericytic stellate cells.","evidence":"Immunohistochemistry, flow cytometry, contractility/migration and tubulogenesis assays with soluble JAM-C; additional Co-IP linking PRL-3 to JAM2 in colon cancer","pmids":["27111582","27588115"],"confidence":"Medium","gaps":["PRL-3/JAM2 interaction rests on a single Co-IP with incomplete pathway placement","Signaling consequences of vessel-wall JAM-B engagement not mapped"]},{"year":2018,"claim":"Demonstrated tissue-level consequences of JAM-B, showing its deficiency reduces liver fibrosis independently of leukocyte infiltration and traps inflammatory cells at CNS borders without blocking BBB crossing, refining JAM-B's role to parenchymal entry.","evidence":"JAM-B knockout mice in autoimmune hepatitis and EAE models, soluble JAM-C treatment, adoptive transfer and CNS cell quantification","pmids":["29753567","29920328"],"confidence":"Medium","gaps":["Molecular step distinguishing border arrest from parenchymal entry unresolved","Cell type providing the JAM-C counter-signal in each context not pinned down"]},{"year":2020,"claim":"Established JAM2 as a human disease gene, showing biallelic loss-of-function (truncations abolishing protein; p.W168C blocking membrane trafficking) causes primary familial brain calcification, with the knockout mouse recapitulating the neuropathology.","evidence":"Whole-genome/exome sequencing, homozygosity mapping, mutant protein expression and localization in CHO cells, patient fibroblasts, and jam2 KO mouse neuropathology","pmids":["31851307","32142645"],"confidence":"High","gaps":["Mechanism linking BBB JAM2 loss to calcification not defined","Cell type within the neurovascular unit driving pathology not isolated"]},{"year":2023,"claim":"Placed JAM2 within a developmental transcriptional program, showing a Pou4f1-Tbr1-Jam2 hierarchy directs formation of orientation-selective retinal ganglion cells.","evidence":"CUT&Tag of Pou4f1 binding, Pou4f1 knockout, enhancer reporter assays","pmids":["38469155"],"confidence":"Medium","gaps":["Adhesive function of JAM2 in J-RGC wiring not directly tested","Downstream effectors of JAM2 in these neurons unknown"]},{"year":2025,"claim":"Identified a vasculogenic role for the JAM2 ortholog, placing Jam2b downstream of Hand2 and upstream of Etv2 for secondary vascular field progenitor emergence and intestinal vascularization.","evidence":"Zebrafish lineage tracing, double maternal-zygotic jam2a;jam2b mutants, hand2 loss-of-function (preprint)","pmids":["41278682"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Whether JAM2 acts via adhesion or signaling in progenitor emergence unresolved","Mammalian conservation untested"]},{"year":null,"claim":"How JAM-B/JAM-C heterodimer disruption is physiologically triggered, and the precise molecular step by which JAM-B licenses leukocyte parenchymal entry and contributes to brain calcification, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the JAM-B/JAM-C/integrin switch","Downstream signaling from JAM-B engagement uncharacterized","Link between BBB tight-junction loss and calcification mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,5,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,22]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,4]}],"complexes":[],"partners":["JAM3","ITGA4","PARD3","TJP1","PTP4A3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P57087","full_name":"Junctional adhesion molecule B","aliases":["Junctional adhesion molecule 2","JAM-2","Vascular endothelial junction-associated molecule","VE-JAM"],"length_aa":298,"mass_kda":33.2,"function":"Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM3 to regulate different cellular processes (PubMed:11590146, PubMed:11823489, PubMed:24357068). Plays a role in homing and mobilization of hematopoietic stem and progenitor cells within the bone marrow (PubMed:24357068). At the surface of bone marrow stromal cells, it contributes to the retention of the hematopoietic stem and progenitor cells expressing JAM3 (PubMed:11590146, PubMed:24357068). Plays a central role in leukocytes extravasation by facilitating not only transmigration but also tethering and rolling of leukocytes along the endothelium (PubMed:12239159). Tethering and rolling of leukocytes are dependent on the binding by JAM2 of the integrin alpha-4/beta-1 (PubMed:12070135). Plays a role in spermatogenesis where JAM2 and JAM3, which are respectively expressed by Sertoli and germ cells, mediate an interaction between both cell types and play an essential role in the anchorage of germ cells onto Sertoli cells and the assembly of cell polarity complexes during spermatid differentiation (By similarity). Also functions as an inhibitory somatodendritic cue that prevents the myelination of non-axonal parts of neurons (By similarity). During myogenesis, it is involved in myocyte fusion (By similarity). May also play a role in angiogenesis (By similarity)","subcellular_location":"Cell membrane; Cell junction; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/P57087/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JAM2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/JAM2","total_profiled":1310},"omim":[{"mim_id":"618824","title":"BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 8, AUTOSOMAL RECESSIVE; IBGC8","url":"https://www.omim.org/entry/618824"},{"mim_id":"606871","title":"JUNCTIONAL ADHESION MOLECULE 3; JAM3","url":"https://www.omim.org/entry/606871"},{"mim_id":"606870","title":"JUNCTIONAL ADHESION MOLECULE 2; JAM2","url":"https://www.omim.org/entry/606870"},{"mim_id":"605721","title":"JUNCTION ADHESION MOLECULE 1; JAM1","url":"https://www.omim.org/entry/605721"},{"mim_id":"213600","title":"BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1; IBGC1","url":"https://www.omim.org/entry/213600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":59.6}],"url":"https://www.proteinatlas.org/search/JAM2"},"hgnc":{"alias_symbol":["VE-JAM","JAM-B","JAMB","CD322","JAM-2"],"prev_symbol":["C21orf43"]},"alphafold":{"accession":"P57087","domains":[{"cath_id":"2.60.40.10","chopping":"35-131","consensus_level":"medium","plddt":92.5734,"start":35,"end":131},{"cath_id":"2.60.40.10","chopping":"137-232","consensus_level":"high","plddt":92.684,"start":137,"end":232}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P57087","model_url":"https://alphafold.ebi.ac.uk/files/AF-P57087-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P57087-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JAM2","jax_strain_url":"https://www.jax.org/strain/search?query=JAM2"},"sequence":{"accession":"P57087","fasta_url":"https://rest.uniprot.org/uniprotkb/P57087.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P57087/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P57087"}},"corpus_meta":[{"pmid":"12953056","id":"PMC_12953056","title":"The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12953056","citation_count":204,"is_preprint":false},{"pmid":"11053409","id":"PMC_11053409","title":"JAM-2, a novel immunoglobulin superfamily molecule, expressed by endothelial and lymphatic cells.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11053409","citation_count":189,"is_preprint":false},{"pmid":"11590146","id":"PMC_11590146","title":"Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11590146","citation_count":172,"is_preprint":false},{"pmid":"12070135","id":"PMC_12070135","title":"JAM2 interacts with alpha4beta1. 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may be due to a founder mutation.","date":"2024","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/38441788","citation_count":4,"is_preprint":false},{"pmid":"40420242","id":"PMC_40420242","title":"Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation.","date":"2025","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/40420242","citation_count":3,"is_preprint":false},{"pmid":"39838844","id":"PMC_39838844","title":"Aberrant Expression of JAM2 Inhibits Invasion and Migration in Lung Adenocarcinoma.","date":"2025","source":"Cancer reports (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/39838844","citation_count":1,"is_preprint":false},{"pmid":"22180727","id":"PMC_22180727","title":"Jamb and jamc muscle in on myoblast fusion.","date":"2011","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/22180727","citation_count":1,"is_preprint":false},{"pmid":"35955781","id":"PMC_35955781","title":"Transcriptional and Post-Translational Regulation of Junctional Adhesion Molecule-B (JAM-B) in Leukocytes under Inflammatory Stimuli.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35955781","citation_count":0,"is_preprint":false},{"pmid":"40159633","id":"PMC_40159633","title":"Clinical Significance of JAM-2 Expression in the Vaginal Wall Tissues of Patients With Pelvic Organ Prolapse.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40159633","citation_count":0,"is_preprint":false},{"pmid":"41278682","id":"PMC_41278682","title":"Jam2 Signaling Functions Downstream of Hand2 To Initiate The Formation Of Organ-Specific Vascular Progenitors In Zebrafish.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41278682","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.12.681872","title":"pI as a Potential Factor Influencing Evolutionary Residue Selection and Structural Stability Among Junctional Adhesion Molecules","date":"2025-10-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.12.681872","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.12.669603","title":"Interactions between tick-borne encephalitis virus non-structural protein 1 and blood-brain barrier tight junction proteins: potential clues to strain-specific neuropathogenicity","date":"2025-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.12.669603","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25094,"output_tokens":6013,"usd":0.082739,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14920,"output_tokens":5244,"usd":0.10285,"stage2_stop_reason":"end_turn"},"total_usd":0.185589,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"JAM-2 localizes to tight junctional complexes of polarized cells and newly formed cell-cell contacts within minutes, and its expression reduces paracellular permeability of cell monolayers, indicating a role in interendothelial junctional complex sealing.\",\n      \"method\": \"Real-time video microscopy, transfection of JAM-2 cDNA into cell monolayers with permeability assays, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment tied to functional consequence (permeability), single lab, two orthogonal methods\",\n      \"pmids\": [\"11053409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"JAM3 is the heterotypic counter-receptor for JAM2; JAM3 ectodomain binds firmly to JAM2-Fc, and JAM3 expressed on T cells mediates JAM2 adhesion, identifying JAM3 as the 43-kDa counter-receptor on lymphocytes.\",\n      \"method\": \"Fc-fusion pulldown (JAM2-Fc capturing JAM3), static adhesion assays with JAM3-expressing cells, polyclonal anti-JAM3 serum blocking experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding assays with Fc fusions, cell adhesion assays, and antibody blocking; independently corroborated by multiple subsequent studies\",\n      \"pmids\": [\"11590146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"JAM2 interacts with α4β1 integrin on T cells, but this interaction requires prior heterotypic engagement of JAM2 with JAM3; the first Ig-like fold of JAM2 is sufficient for binding both JAM3 and α4β1, and Asp-82 in the C-D loop is not required for α4β1 binding.\",\n      \"method\": \"Neutralizing integrin antibodies, small-molecule integrin inhibitor (TBC 772), JAM3 blocking serum, JAM2 domain/point mutants in adhesion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal inhibition approaches plus domain mutagenesis identifying the binding fold and ruling out a specific residue\",\n      \"pmids\": [\"12070135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"VE-JAM/JAM2 mediates adhesion to T cells, NK cells, and dendritic cells through heterotypic interaction with JAM3 expressed on those immune cells.\",\n      \"method\": \"Cell adhesion assays, antibody blocking, JAM3 cloning and functional characterization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell adhesion functional assays with receptor identification, single lab, consistent with concurrent reports\",\n      \"pmids\": [\"11823489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JAM-2 directly associates with the cell polarity protein PAR-3 via the first PDZ domain of PAR-3; JAM-2 also associates with ZO-1 in a PDZ domain-dependent manner. Junctional clustering of JAM-2 (regulated by serine phosphorylation) recruits endogenous PAR-3 and ZO-1 to cell-cell contacts in CHO cells.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression of JAM-2 in CHO cells, immunofluorescence localization, PDZ domain deletion mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-deletion mapping, and functional localization experiments in ectopic expression system; independently consistent with JAM-1/PAR-3 work from same group\",\n      \"pmids\": [\"12953056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"JAM-B (JAM2) and JAM-C undergo heterophilic interaction at cell-cell contacts; JAM-B recruits and stabilizes JAM-C in junctional complexes. Soluble JAM-B dissociates JAM-C homodimers to form JAM-B/JAM-C heterodimers, indicating higher affinity of JAM-C for JAM-B than for itself. Disrupting JAM-B/JAM-C heterodimers with anti-JAM-C antibodies liberates JAM-C to the apical surface, enabling interaction with the leukocyte counter-receptor αMβ2 integrin.\",\n      \"method\": \"Cell-cell contact co-localization, soluble protein competition assays, antibody-mediated complex disruption, αMβ2-dependent leukocyte adhesion assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding competition, antibody disruption, functional adhesion readout) establishing a mechanistic regulatory model\",\n      \"pmids\": [\"16093349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In vivo blockade of JAM-B (using neutralizing antibodies) reduces leukocyte extravasation into the skin and attenuates allergic contact dermatitis; combined JAM-B and JAM-C blockade produces additive inhibition, indicating distinct functions for each molecule in cutaneous inflammation.\",\n      \"method\": \"In vivo antibody blockade in murine allergic contact dermatitis model, histology, enzyme activity assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional blockade with defined cellular phenotype (leukocyte infiltration), single lab\",\n      \"pmids\": [\"16297198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Jam-B (JAM2) is specifically expressed in undifferentiated embryonic stem cells, but Jam-B knockout mice are fertile with no overt developmental defects, and neural and hematopoietic stem cells from knockout mice show normal self-renewal and differentiation, demonstrating JAM-B is dispensable for stem cell identity.\",\n      \"method\": \"DNA microarray expression profiling, Jam-B homozygous knockout mouse generation, stem cell self-renewal and differentiation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple stem cell lineage readouts; negative result is mechanistically informative and robustly established\",\n      \"pmids\": [\"16914739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JAM-B supports lymphocyte rolling and firm adhesion through interaction with α4β1 (VLA-4) integrin; blocking JAM-B in vivo reduces rolling interactions in skin microvasculature and impairs sensitization phase of contact hypersensitivity.\",\n      \"method\": \"Intravital microscopy, dynamic flow chamber T-lymphocyte perfusion over JAM-B-coated slides, integrin-blocking antibodies, adoptive transfer experiments\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including in vitro flow chamber, integrin blocking, and in vivo intravital microscopy with functional immune readout\",\n      \"pmids\": [\"19740376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish jamb and jamc are essential for myocyte fusion to form syncytial muscle fibres; the encoded receptors physically interact and must engage in trans between neighbouring cells for fusion to occur. Loss of either gene results in mononuclear fast-twitch muscle fibres without other overt defects.\",\n      \"method\": \"Heritable zebrafish mutations, in vivo muscle development analysis, cell transplantation (trans interaction requirement), dynamic co-expression analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function with specific cellular phenotype, trans-interaction requirement established by transplantation, physical interaction confirmed\",\n      \"pmids\": [\"22180726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Jam-B/Jam-C interaction between hematopoietic stem/progenitor cells (HSPC) and bone marrow stromal cells is required for HSPC homing and reconstitution; blocking Jam-C with a monoclonal antibody inhibits reconstitution and progenitor homing in a Jam-B-dependent manner and induces HSPC mobilization. The functional adhesive interaction between JAM-B and JAM-C exists between human HSPC and mesenchymal stem cells but not endothelial cells or osteoblasts.\",\n      \"method\": \"Blocking monoclonal antibody against Jam-C, bone marrow reconstitution assays after irradiation, HSPC mobilization measurements, adhesion assays between human cell types\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking antibody with defined cellular phenotype (homing, reconstitution), JAM-B dependence demonstrated, single lab\",\n      \"pmids\": [\"24357068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TGF-β3 suppresses JAM-B expression via two mechanisms: (1) post-translational degradation through the ubiquitin-proteasome pathway requiring Smad signaling, and (2) mRNA destabilization requiring ERK1/2 and p54 JNK activation. Blockade of the ubiquitin-proteasome pathway abrogates TGF-β3-induced loss of JAM-B at cell-cell interfaces in Sertoli cells.\",\n      \"method\": \"Pharmacological inhibitors, siRNA knockdown of Smad and kinases, co-immunoprecipitation, mRNA stability assay, immunofluorescence staining\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mRNA stability assay, proteasome inhibition, siRNA, Co-IP) establishing two distinct regulatory mechanisms\",\n      \"pmids\": [\"25817991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JAM-2 is expressed somatodendritically in neurons and acts as an inhibitory myelin-guidance molecule that prevents oligodendrocyte myelination of the somatodendritic compartment; disruption of dynamic neuron-oligodendrocyte signaling leads to aberrant myelination of somata and dendrites.\",\n      \"method\": \"Purified spinal cord neuron-oligodendrocyte myelinating co-culture, chemical cross-linking, next-generation sequencing, candidate profiling\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-culture system with defined myelination phenotype, candidate identification by sequencing; single lab\",\n      \"pmids\": [\"27499083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRL-3 (PTP4A3) physically interacts with JAM2 in colon cancer cells, as shown by co-immunoprecipitation and immunofluorescence; PRL-3 expression affects cell motility, spreading speed, and cell-matrix adhesion.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, cell wounding assay, cell spread assay, cell-matrix adhesion assay\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying interaction, functional assays present but pathway placement is incomplete, single lab\",\n      \"pmids\": [\"27588115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"During hepatic fibrogenesis, JAM-C is de novo expressed on myofibroblastic hepatic stellate cells, linking them as pericytes to JAM-B-positive endothelial cells; soluble JAM-C blocks stellate cell contractility, increases motility, and reduces endothelial tubulogenesis and endothelial-stellate cell interaction, indicating JAM-B/JAM-C interaction stabilizes vessel walls.\",\n      \"method\": \"Immunohistochemistry, flow cytometry, contractility and migration assays, endothelial tubulogenesis assay, soluble JAM-C treatment\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with soluble protein disruption, cell-type-specific expression localization, single lab\",\n      \"pmids\": [\"27111582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JAM-B deficiency in mice (JAM-B−/−) ameliorates autoimmune-mediated liver fibrosis in a model of autoimmune hepatitis, and soluble recombinant JAM-C also reduces fibrosis; this effect is independent of leukocyte infiltration, suggesting JAM-B/JAM-C interactions directly contribute to fibrotic remodeling rather than through leukocyte recruitment.\",\n      \"method\": \"JAM-B knockout mice, autoimmune hepatitis mouse model, soluble recombinant JAM-C treatment, histological quantification of fibrosis and leukocyte infiltration\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined phenotype and orthogonal soluble protein intervention; single lab\",\n      \"pmids\": [\"29753567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In JAM-B−/− mice subjected to EAE, inflammatory cells accumulate in leptomeningeal and perivascular spaces but fail to enter the CNS parenchyma, ameliorating EAE. JAM-B is not required for CD4+ T-cell arrest or extravasation across the BBB endothelium, but its absence traps cells at CNS border zones, indicating JAM-B facilitates parenchymal entry rather than initial BBB crossing.\",\n      \"method\": \"JAM-B knockout mice, EAE induction with MOG peptide, adoptive transfer of CD4+ T cells, immunofluorescence, flow cytometry of CNS infiltrating cells\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with specific cellular phenotype and mechanistic distinction (parenchymal entry vs BBB crossing), single lab\",\n      \"pmids\": [\"29920328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification (PFBC); truncating mutations (p.L48*, p.M1?) abolish protein expression, and the p.W168C missense mutation prevents JAM2 protein translocation to the plasma membrane, implicating JAM2 in neurovascular unit integrity.\",\n      \"method\": \"Whole genome sequencing, homozygosity mapping, Western blot of mutant proteins in transfected CHO cells, immunofluorescence of mutant protein localization\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics linked to cellular mechanism (loss of membrane localization for missense mutant, loss of protein for truncating mutants), replicated across multiple unrelated families and independently confirmed in a separate study\",\n      \"pmids\": [\"31851307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic JAM2 variants cause loss of JAM2 mRNA expression and absence of JAM2 protein in patient fibroblasts (loss-of-function mechanism); the jam2 complete knockout mouse recapitulates the human PFBC phenotype with vacuolation, reactive astrogliosis, and neuronal density reduction, establishing JAM2 as a blood-brain barrier tight-junction protein required for CNS homeostasis.\",\n      \"method\": \"Exome sequencing with homozygosity mapping, patient fibroblast mRNA and protein expression analysis, jam2 KO mouse neuropathology\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived cell mechanistic validation plus in vivo KO mouse phenotypic confirmation; independently replicates findings of concurrent study (PMID 31851307)\",\n      \"pmids\": [\"32142645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAM-B silencing in pancreatic cancer cells reduces cell migration and invasion, and decreases expression of c-Src and MMP9, placing JAM-B upstream of the c-Src/MMP9 signaling pathway in pancreatic cancer invasion.\",\n      \"method\": \"shRNA-mediated JAM-B silencing, scratch wound assays, Transwell invasion assays, subcutaneous xenograft mouse model, immunohistochemistry for c-Src and MMP9\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with phenotypic readout and pathway markers but no direct mechanistic linkage established\",\n      \"pmids\": [\"32231730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lactobacillus johnsonii GAPDH (moonlighting surface protein) physically binds JAM-2 on mouse gut epithelial cells; this interaction is associated with repair of damaged tight junctions and upregulation of tight junction genes in Caco-2 cells.\",\n      \"method\": \"Affinity resin pulldown of gut surface proteins, protein identification by mass spectrometry, Caco-2 cell barrier repair assay, RNA sequencing\",\n      \"journal\": \"Food & function\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single affinity pulldown identifying the interaction; functional consequence shown indirectly, single lab\",\n      \"pmids\": [\"36069670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In leukocytes, JAM-B protein localizes to the cytoplasm, Golgi apparatus, and nucleus (around ring-shaped structures); nuclear localization occurs via the classical importin-α/β pathway mediated through JAM-B nuclear localization and export signals. Under inflammatory stimuli, JAM-B transcription is regulated via NF-κB-dependent pathways, and at the post-translational level JAM-B is regulated by ubiquitin-proteasome pathways involving APC/C (ubiquitination) and HAUSP/USP7 (de-ubiquitination).\",\n      \"method\": \"Immunoassays, qPCR, pharmacological inhibitors of importin pathway and NF-κB signaling, proteasome inhibitors\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor-based pathway assignment, single lab, no direct mutagenesis of NLS/NES signals or ubiquitin site mapping\",\n      \"pmids\": [\"35955781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A Pou4f1-Tbr1-Jam2 transcriptional hierarchy controls formation of JAM2-expressing orientation-selective retinal ganglion cells (J-RGCs); Pou4f1 directly binds regulatory elements of both Tbr1 and Jam2 (identified by CUT&Tag), and Pou4f1 is required for expression of Tbr1 and Jam2 in J-RGCs.\",\n      \"method\": \"CUT&Tag chromatin profiling of Pou4f1 binding sites, genetic loss-of-function (Pou4f1 knockout), reporter gene assays for enhancer activity\",\n      \"journal\": \"Frontiers in ophthalmology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag plus KO plus reporter assay establishing direct upstream transcriptional regulation; single lab\",\n      \"pmids\": [\"38469155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, Jam2b (ortholog of human JAM2) functions downstream of the transcription factor Hand2 and is required for emergence of secondary vascular field (SVF) endothelial progenitors that give rise to intestinal vasculature; double maternal-zygotic jam2a;jam2b mutants show greatly reduced SVF cells and defective intestinal vasculature. Hand2 is required to induce Jam2b expression and the downstream vasculogenic transcription factor Etv2/Etsrp.\",\n      \"method\": \"Time-lapse imaging, jam2b:Cre lineage tracing, double maternal-zygotic jam2a;jam2b mutant zebrafish, hand2 loss-of-function, etv2 expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with lineage tracing and time-lapse; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41278682\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"JAM2 (JAM-B) is a transmembrane immunoglobulin superfamily adhesion molecule that forms heterodimeric complexes with JAM3 (JAM-C) via its first Ig-like fold, recruits polarity proteins PAR-3 and ZO-1 through PDZ domain interactions (regulated by serine phosphorylation), engages α4β1 integrin on leukocytes (facilitated by prior JAM3 binding), acts as an inhibitory somatodendritic cue preventing aberrant oligodendrocyte myelination, is essential for vertebrate myocyte fusion (acting in trans with JAM-C), contributes to neurovascular unit integrity and blood-brain barrier paracellular function (biallelic loss causes primary familial brain calcification), and its expression is regulated post-translationally by TGF-β3 via Smad-dependent ubiquitin-proteasome degradation and ERK/JNK-mediated mRNA destabilization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JAM2 (JAM-B) is a tight-junction-associated immunoglobulin-superfamily adhesion molecule that seals interendothelial/interepithelial junctions and couples cell-cell adhesion to leukocyte trafficking, myogenesis, and neurovascular integrity [#0, #1]. Its principal binding partner is JAM3 (JAM-C): the JAM-B ectodomain forms high-affinity heterodimers that recruit and stabilize JAM-C in junctional complexes, and JAM-B's first Ig-like fold mediates both this heterotypic interaction and a JAM3-dependent engagement of \\u03b14\\u03b21 (VLA-4) integrin on lymphocytes [#1, #2, #5]. Through serine-phosphorylation-regulated junctional clustering, JAM-2 binds the polarity protein PAR-3 and ZO-1 via PDZ-domain interactions, recruiting them to nascent cell-cell contacts [#4]. Functionally, JAM-B supports lymphocyte rolling and firm adhesion and promotes leukocyte entry into tissue and the CNS parenchyma without being required for the initial BBB crossing [#8, #16], and acts in trans with JAM-C to drive myocyte fusion into syncytial muscle fibres [#9]. In the nervous system JAM-2 is a somatodendritic inhibitory cue that prevents oligodendrocyte myelination of neuronal somata and dendrites [#12]. Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification, with truncating alleles abolishing protein and a missense allele (p.W168C) blocking trafficking to the plasma membrane, and the knockout mouse recapitulates the neuropathology, establishing JAM2 as a blood-brain-barrier tight-junction protein required for CNS homeostasis [#17, #18]. JAM-B expression is post-translationally suppressed by TGF-\\u03b23 through Smad-dependent ubiquitin-proteasome degradation and ERK/JNK-mediated mRNA destabilization [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that JAM-2 is a junctional component whose expression actively seals paracellular barriers, defining its baseline role in tight-junction integrity.\",\n      \"evidence\": \"Real-time video microscopy and permeability assays in JAM-2-transfected monolayers\",\n      \"pmids\": [\"11053409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify binding partners mediating the sealing\", \"No in vivo barrier validation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified JAM3 as the heterotypic counter-receptor for JAM2, answering what molecule JAM2 engages on apposed cells and lymphocytes.\",\n      \"evidence\": \"JAM2-Fc pulldown, static adhesion assays with JAM3-expressing T cells, antibody blocking\",\n      \"pmids\": [\"11590146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and stoichiometry of the heterodimer not quantified\", \"Structural basis of binding not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed JAM2 additionally engages \\u03b14\\u03b21 integrin on leukocytes but only after prior JAM3 binding, and mapped both interactions to the first Ig-like fold, linking adhesion architecture to leukocyte recruitment.\",\n      \"evidence\": \"Integrin-blocking antibodies, small-molecule inhibitor, JAM3 blocking serum, and JAM2 domain/point mutants in adhesion assays; concurrent immune-cell adhesion characterization\",\n      \"pmids\": [\"12070135\", \"11823489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational change converting JAM2 to an integrin ligand not defined\", \"In vivo relevance of integrin engagement not yet tested in this work\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected JAM2 adhesion to intracellular polarity machinery by demonstrating phosphorylation-regulated, PDZ-dependent recruitment of PAR-3 and ZO-1, explaining how junctional JAM2 organizes the contact site.\",\n      \"evidence\": \"Co-immunoprecipitation, PDZ-domain deletion mutants, and immunofluorescence in CHO cells ectopically expressing JAM-2\",\n      \"pmids\": [\"12953056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase controlling the regulatory serine phosphorylation not identified\", \"Done in ectopic CHO system, not native junctions\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the regulatory logic of the JAM-B/JAM-C heterodimer\\u2014JAM-B sequesters JAM-C, and disrupting the pair liberates JAM-C to engage \\u03b1M\\u03b22 integrin\\u2014establishing JAM-B as a gatekeeper of leukocyte adhesion; in vivo blockade reduced leukocyte extravasation in skin.\",\n      \"evidence\": \"Soluble protein competition, antibody-mediated complex disruption, \\u03b1M\\u03b22 adhesion assays; murine allergic contact dermatitis blockade\",\n      \"pmids\": [\"16093349\", \"16297198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for physiological heterodimer disruption in vivo unknown\", \"Quantitative affinity differences inferred from competition, not direct binding constants\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tested whether the embryonic-stem-cell-enriched JAM-B is required for stemness, finding it dispensable for stem cell self-renewal and differentiation, narrowing its functional scope.\",\n      \"evidence\": \"Jam-B knockout mice with neural and hematopoietic stem cell self-renewal/differentiation assays\",\n      \"pmids\": [\"16914739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address adhesion functions of JAM-B in other tissues\", \"Possible redundancy with related JAMs not examined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the dynamic step of leukocyte trafficking that JAM-B controls, showing it supports both rolling and firm adhesion via \\u03b14\\u03b21 in skin microvasculature and is required for contact-hypersensitivity sensitization.\",\n      \"evidence\": \"Intravital microscopy, flow-chamber lymphocyte perfusion over JAM-B, integrin blockade, adoptive transfer\",\n      \"pmids\": [\"19740376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of JAM3 versus integrin engagement in vivo not separated\", \"Endothelial signaling downstream of JAM-B engagement unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a developmental, non-immune role: JAM-B and JAM-C must interact in trans between adjacent myoblasts to drive myocyte fusion, defining a requirement for syncytial muscle formation.\",\n      \"evidence\": \"Heritable zebrafish jamb/jamc mutants, cell transplantation establishing trans requirement, physical interaction analysis\",\n      \"pmids\": [\"22180726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fusogenic machinery downstream of JAM engagement not identified\", \"Conservation of myocyte-fusion role in mammals not addressed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended JAM-B/JAM-C adhesion to the bone marrow niche, showing the interaction between HSPCs and stromal/mesenchymal cells is required for homing and reconstitution.\",\n      \"evidence\": \"Anti-Jam-C blocking antibody, bone marrow reconstitution and homing assays, human cell-type adhesion comparisons\",\n      \"pmids\": [\"24357068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAM-B-side signaling in HSPCs not dissected\", \"Single lab, blocking-antibody-based\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined how JAM-B levels are controlled, showing TGF-\\u03b23 suppresses JAM-B by two parallel routes\\u2014Smad-dependent ubiquitin-proteasome degradation and ERK/JNK-driven mRNA destabilization.\",\n      \"evidence\": \"Pharmacological inhibitors, siRNA against Smad and kinases, Co-IP, mRNA stability assays in Sertoli cells\",\n      \"pmids\": [\"25817991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating degradation not identified\", \"Generality beyond Sertoli cells not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified JAM-2 as a somatodendritic inhibitory myelin-guidance cue, answering how neurons restrict oligodendrocyte myelination to axons.\",\n      \"evidence\": \"Neuron-oligodendrocyte myelinating co-culture, chemical cross-linking, candidate sequencing\",\n      \"pmids\": [\"27499083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligodendrocyte-side receptor not defined in this work\", \"Downstream inhibitory signaling pathway unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated JAM-B/JAM-C adhesion in vascular wall stabilization during fibrogenesis, linking JAM-B-positive endothelium to JAM-C-expressing pericytic stellate cells.\",\n      \"evidence\": \"Immunohistochemistry, flow cytometry, contractility/migration and tubulogenesis assays with soluble JAM-C; additional Co-IP linking PRL-3 to JAM2 in colon cancer\",\n      \"pmids\": [\"27111582\", \"27588115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PRL-3/JAM2 interaction rests on a single Co-IP with incomplete pathway placement\", \"Signaling consequences of vessel-wall JAM-B engagement not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated tissue-level consequences of JAM-B, showing its deficiency reduces liver fibrosis independently of leukocyte infiltration and traps inflammatory cells at CNS borders without blocking BBB crossing, refining JAM-B's role to parenchymal entry.\",\n      \"evidence\": \"JAM-B knockout mice in autoimmune hepatitis and EAE models, soluble JAM-C treatment, adoptive transfer and CNS cell quantification\",\n      \"pmids\": [\"29753567\", \"29920328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step distinguishing border arrest from parenchymal entry unresolved\", \"Cell type providing the JAM-C counter-signal in each context not pinned down\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established JAM2 as a human disease gene, showing biallelic loss-of-function (truncations abolishing protein; p.W168C blocking membrane trafficking) causes primary familial brain calcification, with the knockout mouse recapitulating the neuropathology.\",\n      \"evidence\": \"Whole-genome/exome sequencing, homozygosity mapping, mutant protein expression and localization in CHO cells, patient fibroblasts, and jam2 KO mouse neuropathology\",\n      \"pmids\": [\"31851307\", \"32142645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking BBB JAM2 loss to calcification not defined\", \"Cell type within the neurovascular unit driving pathology not isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed JAM2 within a developmental transcriptional program, showing a Pou4f1-Tbr1-Jam2 hierarchy directs formation of orientation-selective retinal ganglion cells.\",\n      \"evidence\": \"CUT&Tag of Pou4f1 binding, Pou4f1 knockout, enhancer reporter assays\",\n      \"pmids\": [\"38469155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adhesive function of JAM2 in J-RGC wiring not directly tested\", \"Downstream effectors of JAM2 in these neurons unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a vasculogenic role for the JAM2 ortholog, placing Jam2b downstream of Hand2 and upstream of Etv2 for secondary vascular field progenitor emergence and intestinal vascularization.\",\n      \"evidence\": \"Zebrafish lineage tracing, double maternal-zygotic jam2a;jam2b mutants, hand2 loss-of-function (preprint)\",\n      \"pmids\": [\"41278682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Whether JAM2 acts via adhesion or signaling in progenitor emergence unresolved\", \"Mammalian conservation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JAM-B/JAM-C heterodimer disruption is physiologically triggered, and the precise molecular step by which JAM-B licenses leukocyte parenchymal entry and contributes to brain calcification, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the JAM-B/JAM-C/integrin switch\", \"Downstream signaling from JAM-B engagement uncharacterized\", \"Link between BBB tight-junction loss and calcification mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 5, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 22]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JAM3\", \"ITGA4\", \"PARD3\", \"TJP1\", \"PTP4A3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}