{"gene":"JAG2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"JAG2 and DLL1 act synergistically as Notch ligands to regulate hair cell differentiation in the cochlea via lateral inhibition; genetic epistasis and conditional inactivation showed both ligands signal primarily through the NOTCH1 receptor. Supernumerary hair cells in double mutants arise through cell fate switching rather than excess proliferation.","method":"Genetic epistasis (Dll1/Jag2 double mutant mice), conditional inactivation of Notch1","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis with double mutants and conditional receptor knockout, replicated across multiple allele combinations","pmids":["16141228"],"is_preprint":false},{"year":2000,"finding":"JAG2 (Jagged2) functions as a Notch ligand mediating lateral inhibition in cochlear development; loss of Jag2 leads to increased Math1-expressing cells and dramatically reduced HES5 expression in supporting cells, consistent with JAG2-activated Notch suppressing Math1 through HES5.","method":"In situ hybridization in wild-type vs. Jag2 mutant cochleae","journal":"Journal of the Association for Research in Otolaryngology : JARO","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular readouts (Math1, HES5) in a genetic model, single lab","pmids":["11545143"],"is_preprint":false},{"year":2006,"finding":"JAG2 is required for Notch1 activation in oral periderm cells during palatogenesis; Jag2 mutants show significantly attenuated Notch1 activation in oral epithelium and defective periderm differentiation, causing palate-tongue fusions. Recombinant explant cultures confirmed the Jag2 mutant tongue fuses to wild-type palatal shelves.","method":"Jag2 knockout mouse analysis, molecular marker analysis, recombinant explant co-culture","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model combined with ex vivo recombinant explant assay and molecular pathway validation (Notch1 activation)","pmids":["16607638"],"is_preprint":false},{"year":2004,"finding":"JAG2 overexpression in multiple myeloma malignant plasma cells induces IL-6, VEGF, and IGF-1 secretion from stromal cells in vitro; this IL-6 induction was blocked by anti-Notch-1 monoclonal antibodies targeting the Notch-1/JAG2 binding sequence, indicating JAG2 signals through NOTCH1. JAG2 overexpression is associated with hypomethylation of its promoter.","method":"In vitro co-culture assay, neutralizing antibody blocking experiment, promoter methylation analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-culture assay with pathway-specific antibody blockade, single lab","pmids":["15292061"],"is_preprint":false},{"year":2009,"finding":"JAG2 promoter is aberrantly acetylated in multiple myeloma due to reduced levels of the SMRT corepressor, which normally recruits HDACs to the JAG2 promoter; restoration of SMRT function induced JAG2 downregulation and MM cell apoptosis.","method":"Chromatin acetylation analysis, SMRT overexpression/restoration, apoptosis assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with defined epigenetic mechanism, single lab, multiple methods","pmids":["19417136"],"is_preprint":false},{"year":2007,"finding":"DeltaNp63 transcription factor enhances Jag2 expression in thymic epithelial cells in vivo; p63-/- thymi show reduced Jag2 expression and reduced γδ T cell formation similar to Jag2-/- thymi, placing JAG2 downstream of DeltaNp63 in thymic development.","method":"Genetic complementation (p63-/- mice crossed with DeltaNp63α or TAp63α transgenic mice), in vivo gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via in vivo complementation, single lab","pmids":["17626181"],"is_preprint":false},{"year":2010,"finding":"JAG2 is a direct transcriptional target of ectopic MYC in human B cells; JAG2 expression promotes hypoxic cell proliferation and in vivo tumorigenesis. RNAi targeting JAG2 or gamma-secretase inhibitor DAPT preferentially inhibited the neoplastic (Myc-high) state.","method":"Inducible Myc expression system (P493-6 cells), RNAi knockdown, gamma-secretase inhibitor treatment, in vivo xenograft assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Myc-inducible system with RNAi and pharmacological inhibition plus in vivo validation, single lab","pmids":["20133585"],"is_preprint":false},{"year":2011,"finding":"JAG2 is transcriptionally activated by hypoxia in a HIF-1α-dependent manner; hypoxic JAG2 induction increases NOTCH1 intracellular domain levels and HEY1 expression in tumor cells, and JAG2 siRNA knockdown in breast cancer cells reduces endothelial capillary tube formation in co-culture.","method":"HIF-1α siRNA knockdown, Notch target gene expression analysis (icN1, HEY1), JAG2 siRNA + endothelial co-culture tube formation assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HIF-1α-dependence established by knockdown, functional consequence shown in co-culture, single lab","pmids":["21402725"],"is_preprint":false},{"year":2012,"finding":"JAG2 expression is required for clonogenic (self-renewal) growth of myeloma cells; silencing JAG2 blocked colony formation in vitro and in vivo tumor formation in immunocompromised mice. Blocking JAG-NOTCH interactions with NOTCH-Fc chimeric molecules also impaired colony formation.","method":"JAG2 siRNA knockdown, NOTCH-Fc chimeric molecule blocking, colony formation assay, in vivo xenograft","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function by RNAi and pathway blockade with in vivo confirmation, single lab","pmids":["22341562"],"is_preprint":false},{"year":2013,"finding":"JAG2 promotes invasion, migration, and clonogenic growth in uveal melanoma cells; JAG2 overexpression increases Hes1 mRNA (a Notch target), and shRNA-mediated knockdown suppresses growth, invasion, and migration. JAG2 and Hes1 mRNA are enriched in invasive cells that pass through Matrigel.","method":"JAG2-GFP-MSCV overexpression, sh-JAG2 knockdown, transwell invasion/wound-healing assays, soft agar colony assay","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined cellular phenotypes, single lab","pmids":["23211831"],"is_preprint":false},{"year":2014,"finding":"BACE1 (β-secretase) does NOT effectively cleave JAG2, in contrast to its cleavage of JAG1, indicating selective protease-mediated regulation between these paralogs; JAG2 ectodomain shedding by BACE1 is absent despite high homology with JAG1.","method":"In vitro BACE1 cleavage assay, comparison between Jag1 and Jag2 substrates, BACE1-null mouse analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay directly comparing JAG1 vs JAG2 as substrates, single lab; finding is a negative result","pmids":["24907271"],"is_preprint":false},{"year":2014,"finding":"JAG2 is a transcriptional target of MYC in medulloblastoma (Group 3/MYC-driven); MYC-induced transcriptional activation of JAG2 was identified as the mechanistic link between MYC oncogene activity and Notch pathway activation in MB cells.","method":"MYC knockdown/overexpression, qPCR, correlation analysis in primary tumor cohorts","journal":"Acta neuropathologica communications","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — MYC-JAG2 transcriptional link shown by expression analysis and knockdown, corroborates Yustein 2010, single lab without direct promoter binding assay","pmids":["24708907"],"is_preprint":false},{"year":2017,"finding":"JAG2 expression in colorectal cancer is regulated by Wnt/β-catenin signaling; pharmacological or genetic inhibition of β-catenin suppressed JAG2 expression, and APC deletion upregulated JAG2. JAG2 modulates chemoresistance through p21: JAG2 knockdown reduced p21, sensitizing cells to chemotherapy, and forced p21 expression rescued sensitivity; p21-null cells were unaffected by JAG2 knockdown.","method":"β-catenin inhibitors, β-catenin siRNA, APC conditional knockout mice, JAG2 knockdown/overexpression, p21 forced expression, chemosensitivity assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between JAG2 and p21 in chemoresistance established by rescue experiment; Wnt regulation confirmed by multiple methods, single lab","pmids":["28881809"],"is_preprint":false},{"year":2019,"finding":"JAG2 activates Notch2/Hes1/Hey2 signaling in nucleus pulposus (NP) cells to promote proliferation; this involves cyclin D1 regulation and activation of PI3K/Akt and Wnt/β-catenin pathways. JAG2/Notch2 signaling inhibits TNF-α-induced apoptosis by suppressing formation of the RIP1-FADD-caspase-8 complex. Intradiscal JAG2 injection alleviated intervertebral disc degeneration in rats.","method":"Recombinant JAG2 treatment, Notch2/Hes1/Hey2 siRNA, cell cycle analysis, PI3K/Akt and Wnt pathway assessment, apoptosis complex immunoprecipitation, in vivo rat disc injection model","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant ligand activation combined with siRNA pathway dissection and in vivo rescue, single lab","pmids":["31619270"],"is_preprint":false},{"year":2019,"finding":"JAG2 promotes migration and invasion of colorectal cancer cells through a non-canonical, Notch-independent and EMT-independent pathway. JAG2 co-expression with PRAF2 was identified; JAG2-rich exosomes are released from CRC cells in a PRAF2-dependent manner, and these exosomes promote metastasis in a paracrine fashion.","method":"siRNA knockdown, transcriptome microarray, exosome isolation and characterization, EMT pathway inhibitors, co-culture assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — JAG2-PRAF2 co-expression and exosome-mediated paracrine mechanism identified using multiple orthogonal approaches, single lab","pmids":["31198409"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function JAG2 variants cause muscular dystrophy associated with misregulation of myogenesis genes including PAX7; Jag2 downregulation in murine myoblasts reduced multiple Notch pathway components including Megf10. Investigations in Drosophila revealed an interaction between Serrate (JAG1/JAG2 ortholog) and Drpr (MEGF10 ortholog), placing JAG2 upstream of MEGF10 in muscle development.","method":"Whole-exome sequencing, transcriptome analysis of patient muscle, Jag2 siRNA knockdown in murine myoblasts, Drosophila genetic interaction assay","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in multiple systems (human patient tissue, mouse myoblasts, Drosophila) with defined molecular phenotypes, single consortium","pmids":["33861953"],"is_preprint":false},{"year":2021,"finding":"MSC secretome activates the IL-6-p-STAT3-p63-JAG2 pathway in lung basal cells; inhibition of IL-6/STAT3 signaling activates p63-JAG2 signaling, promoting p63+ cell proliferation and lung repair. This pathway placement was established in a bleomycin ALI mouse model.","method":"Bleomycin ALI mouse model, intratracheal MSC supernatant lyophilized powder treatment, western blot, immunofluorescence, flow cytometry, qPCR","journal":"Stem cell research & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement (IL-6-STAT3-p63-JAG2) inferred from in vivo treatment model without direct JAG2 manipulation, single lab","pmids":["33781349"],"is_preprint":false},{"year":2022,"finding":"JAG1 and JAG2 undergo posttranslational modifications in tracheobronchial epithelium: gamma-secretase complex and glycogen synthase kinase 3 are implicated in generating a JAG1 C-terminal peptide and regulating full-length JAG2 abundance on the cell surface. These distinct assemblies of JAG1 and JAG2 regulate Notch signal strength and determine cell fate (goblet vs. ciliated cells).","method":"Human air-liquid-interface cultures, gamma-secretase inhibitors, neutralizing antibodies, WNT pathway antagonists/agonists, biochemical fractionation, RNA-Seq","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical evidence for posttranslational regulation of JAG2 surface abundance via GSC/GSK3, multiple pharmacological and molecular tools, single lab","pmids":["35819850"],"is_preprint":false},{"year":2024,"finding":"JAG2/Notch1 is the primary signaling axis promoting sebocyte differentiation in homeostatic mouse skin; specific inhibition of JAG2 ligand (using monoclonal antibody) or Notch1 receptor causes loss of mature sebocytes and accumulation of proliferative progenitor cells. This phenotype is reversible upon removal of inhibition.","method":"Monoclonal antibody-mediated specific inhibition of individual Notch ligands/receptors in vivo (mouse), histological analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand-specific and receptor-specific antibody inhibition in vivo distinguishes JAG2/Notch1 axis from other ligand-receptor pairs, with reversibility control","pmids":["39585329"],"is_preprint":false},{"year":2024,"finding":"NEURL1 and NEURL2 (Neuralized-like proteins) do NOT activate JAG2, because JAG2 lacks the Neuralized binding motif (consensus NxxN) present in DLL1 and JAG1 but absent in DLL4 and JAG2; this was demonstrated using humanized Drosophila and mammalian cell culture assays.","method":"Humanized Drosophila rescue assay, mammalian cell culture Notch activation assay, motif analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay in two systems showing NEURL proteins cannot activate JAG2; negative result with mechanistic basis (missing NxxN motif), preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"Usp11 deubiquitinase sustains marginal zone B cell survival by deubiquitinating JAG2 (and DLL1), thereby maintaining Notch ligand levels; Usp11 knockout mice show increased MZ B cell survival after irradiation, and Co-IP/ubiquitination experiments confirmed the Usp11-JAG2 deubiquitination relationship.","method":"Co-immunoprecipitation, ubiquitination assay, Usp11 knockout mouse model, flow cytometry, immunofluorescence","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay establishing Usp11 as a deubiquitinase for JAG2, supported by in vivo KO model, single lab","pmids":["39904982"],"is_preprint":false},{"year":2025,"finding":"JAG2+ tumor-associated neutrophils activate Notch signaling in CD4+ T cells via RBPJ-mediated transcription, driving their differentiation into effector regulatory T cells (eTregs); this was blocked by Notch inhibitor LY3039478 or JAG2 neutralizing antibodies. JAG2-NOTCH-RBPJ axis in macrophage-adjacent T cells was demonstrated by co-culture and in vivo xenograft models.","method":"In vitro co-culture, flow cytometry, Notch inhibitor LY3039478, JAG2 neutralizing antibodies, xenograft and patient-derived tumor organoid models, scRNA-seq","journal":"Cancer communications (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — JAG2-Notch-RBPJ-eTreg axis established with pharmacological and antibody blockade plus in vivo models, single lab","pmids":["40120139"],"is_preprint":false},{"year":2025,"finding":"CD146 activates NF-κB signaling to upregulate JAG2 expression in hepatocellular carcinoma cells; JAG2 in turn activates Notch signaling to increase cancer stem cell stemness and chemoresistance. JAG2 overexpression rescued stemness and chemoresistance lost upon CD146 knockdown, placing JAG2 downstream of CD146-NF-κB.","method":"CD146 knockdown/overexpression, JAG2 overexpression rescue, NF-κB pathway analysis, in vitro stemness and chemoresistance assays, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiment placing JAG2 downstream of CD146-NF-κB, single lab","pmids":["40032820"],"is_preprint":false},{"year":2025,"finding":"Tumor-derived JAG2 signals through macrophage NOTCH3 to induce STAT3 phosphorylation and CCL2 upregulation in macrophages, promoting an immunosuppressive M2-like/neurotrophic phenotype that facilitates perineural invasion in colorectal cancer. Disruption of JAG2-NOTCH3 signaling, STAT3 inhibition, or CCL2 blockade attenuated these effects in vitro and in vivo.","method":"Single-cell transcriptomics, ligand-receptor interaction analysis, in vitro JAG2-NOTCH3 activation assays, STAT3 inhibition, CCL2 blockade, in vivo nerve invasion model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — JAG2-NOTCH3-STAT3-CCL2 axis established by multiple inhibition experiments in vitro and in vivo, single lab","pmids":["41916520"],"is_preprint":false},{"year":2026,"finding":"JAG2 deficiency impairs Notch signaling in muscle stem cells (MuSCs) and disrupts myogenic self-renewal and differentiation. In cell-type-specific conditional knockout mice: MuEC-specific Jag2 knockout reduces MuSC self-renewal (trans-activation), while MuSC-specific Jag2 knockout reduces myogenic differentiation (cis-inhibition). Human pathogenic JAG2 variants, but not reference JAG2, fail to rescue Serrate (JAG2 Drosophila ortholog) deficiency, confirming variant-specific loss of function.","method":"Cell-type-specific conditional knockout mice (MuEC- and MuSC-specific), co-culture experiments, Jag2 hypomorphic mouse model, Drosophila rescue assay with pathogenic human JAG2 variants","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockouts distinguishing cis vs trans roles, cross-species rescue with pathogenic variants, multiple orthogonal models in single study","pmids":["42154534"],"is_preprint":false},{"year":2018,"finding":"JAG2 signaling induces CD14+ monocytes to acquire an LCH (Langerhans cell histiocytosis)-like gene signature including CD1a and langerin expression; Notch inhibition suppresses the LCH phenotype, placing JAG2-mediated Notch activation as an initiating event in monocyte-to-LCH-like cell differentiation.","method":"JAG2-stimulated monocyte differentiation assay, gene expression profiling, Notch inhibitor treatment, flow cytometry","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — JAG2-Notch axis causally linked to monocyte differentiation phenotype using both activation and inhibition, single lab","pmids":["30296338"],"is_preprint":false}],"current_model":"JAG2 (Jagged2) is a canonical cell-surface Notch ligand that activates NOTCH1 and NOTCH2 receptors to regulate cell fate decisions in multiple tissues, including cochlear hair cell patterning via lateral inhibition, oral epithelial differentiation, sebaceous gland differentiation (Jag2/Notch1 axis), muscle stem cell self-renewal and differentiation (via cell-type-specific cis-inhibition and trans-activation), and immune cell fate; its expression is transcriptionally induced by MYC and HIF-1α, epigenetically regulated via SMRT-HDAC-dependent promoter acetylation, and its surface abundance is controlled post-translationally by gamma-secretase and glycogen synthase kinase 3, while Usp11 deubiquitinates JAG2 to stabilize it; unlike JAG1, JAG2 is not cleaved by BACE1 and lacks the NxxN Neuralized-binding motif, making it insensitive to NEURL-mediated activation."},"narrative":{"mechanistic_narrative":"JAG2 (Jagged2) is a cell-surface Notch ligand that drives cell-fate decisions across developing epithelia, muscle, and immune compartments by activating Notch receptors on neighboring cells [PMID:16141228, PMID:16607638, PMID:39585329]. In the cochlea it cooperates with DLL1 to signal through NOTCH1 and enforce lateral inhibition, restricting hair cell fate by inducing HES5 and suppressing Math1 [PMID:16141228, PMID:11545143], and analogous JAG2/NOTCH1 lateral-inhibition logic patterns oral periderm during palatogenesis [PMID:16607638] and sebocyte differentiation in skin [PMID:39585329]. In muscle, cell-type-specific knockouts resolve a dual mode of action: JAG2 on muscle endothelial cells trans-activates muscle stem cell self-renewal, while JAG2 on the stem cells themselves cis-inhibits to permit differentiation, and pathogenic human JAG2 variants that fail to rescue the Drosophila ortholog cause muscular dystrophy with PAX7 and MEGF10 misregulation [PMID:33861953, PMID:42154534]. JAG2 also acts as an oncogenic Notch ligand: its transcription is induced by MYC [PMID:20133585], HIF-1α under hypoxia [PMID:21402725], Wnt/β-catenin [PMID:28881809], CD146-NF-κB [PMID:40032820], and DeltaNp63 [PMID:17626181], and is epigenetically derepressed in multiple myeloma through loss of SMRT-HDAC-mediated promoter deacetylation [PMID:19417136]; downstream it activates NOTCH1/NOTCH2/NOTCH3 to support tumor self-renewal, invasion, chemoresistance, and an immunosuppressive microenvironment via effects on T cells and macrophages [PMID:22341562, PMID:23211831, PMID:31619270, PMID:40120139, PMID:41916520]. JAG2 surface abundance is controlled post-translationally by gamma-secretase and GSK3 [PMID:35819850] and stabilized by the deubiquitinase Usp11 [PMID:39904982]; unlike its paralog JAG1, JAG2 is not cleaved by BACE1 [PMID:24907271] and lacks the NxxN motif required for NEURL-mediated activation.","teleology":[{"year":2000,"claim":"Established JAG2 as a functional Notch ligand mediating lateral inhibition during sensory development, defining its core role in restricting cell fate.","evidence":"In situ hybridization comparing wild-type and Jag2 mutant cochleae with Math1/HES5 readouts","pmids":["11545143"],"confidence":"Medium","gaps":["Did not identify the specific Notch receptor engaged","Molecular link to HES5 inferred from expression, not direct receptor activation assay"]},{"year":2005,"claim":"Resolved which receptor JAG2 signals through and the cellular basis of its phenotype, showing JAG2/DLL1 act synergistically via NOTCH1 to switch fate rather than alter proliferation.","evidence":"Genetic epistasis with Dll1/Jag2 double mutant mice and conditional Notch1 inactivation","pmids":["16141228"],"confidence":"High","gaps":["Did not address contribution of NOTCH2/3 in other tissues","Mechanism of ligand cooperation not biochemically defined"]},{"year":2006,"claim":"Extended JAG2-NOTCH1 lateral inhibition to a second developmental context, palatogenesis, establishing its requirement for periderm differentiation.","evidence":"Jag2 knockout mouse analysis with recombinant explant co-culture and Notch1 activation markers","pmids":["16607638"],"confidence":"High","gaps":["Downstream effectors of periderm differentiation not mapped"]},{"year":2007,"claim":"Placed JAG2 downstream of a transcription factor, DeltaNp63, in immune-organ development, beginning to define its upstream regulation.","evidence":"Genetic complementation of p63-/- mice with DeltaNp63α/TAp63α transgenes and in vivo expression analysis","pmids":["17626181"],"confidence":"Medium","gaps":["Direct binding of DeltaNp63 to the JAG2 promoter not shown","γδ T cell defect linked correlatively"]},{"year":2010,"claim":"Identified JAG2 as a direct MYC transcriptional target linking oncogene activity to Notch pathway activation and tumor growth.","evidence":"Inducible Myc system, JAG2 RNAi, gamma-secretase inhibitor DAPT, and xenograft assays","pmids":["20133585"],"confidence":"Medium","gaps":["Receptor identity in this context not pinned","Single cell-line system"]},{"year":2011,"claim":"Showed JAG2 is a hypoxia/HIF-1α-induced ligand with pro-angiogenic consequences, connecting the tumor microenvironment to JAG2-Notch signaling.","evidence":"HIF-1α siRNA knockdown, icN1/HEY1 readouts, JAG2 siRNA endothelial tube-formation co-culture","pmids":["21402725"],"confidence":"Medium","gaps":["Direct HIF-1α binding to JAG2 promoter not demonstrated"]},{"year":2012,"claim":"Defined a functional requirement for JAG2 in cancer self-renewal, showing it sustains clonogenic growth of myeloma cells.","evidence":"JAG2 siRNA, NOTCH-Fc chimeric blockade, colony formation, in vivo xenograft","pmids":["22341562"],"confidence":"Medium","gaps":["Receptor specificity not resolved","Single lab"]},{"year":2009,"claim":"Uncovered an epigenetic mechanism of aberrant JAG2 activation in myeloma via loss of SMRT-recruited HDAC activity at its promoter.","evidence":"Chromatin acetylation analysis, SMRT restoration, apoptosis assay","pmids":["19417136"],"confidence":"Medium","gaps":["Direct SMRT occupancy at JAG2 promoter inferred","Single lab"]},{"year":2014,"claim":"Distinguished JAG2 from its paralog JAG1 at the level of protease regulation, showing JAG2 resists BACE1-mediated shedding.","evidence":"In vitro BACE1 cleavage assay comparing JAG1 vs JAG2 plus BACE1-null mouse analysis","pmids":["24907271"],"confidence":"Medium","gaps":["Negative result; functional consequence of resistance not tested","Other shedding proteases not surveyed"]},{"year":2017,"claim":"Linked Wnt/β-catenin regulation of JAG2 to chemoresistance through a p21-dependent effector arm in colorectal cancer.","evidence":"β-catenin inhibitors/siRNA, APC conditional knockout, JAG2 and p21 manipulation, chemosensitivity assays","pmids":["28881809"],"confidence":"Medium","gaps":["Whether p21 effect requires canonical Notch signaling unclear"]},{"year":2019,"claim":"Revealed both a canonical NOTCH2 anti-apoptotic/proliferative role and a non-canonical Notch-independent exosomal metastasis function for JAG2.","evidence":"Recombinant JAG2 and siRNA in nucleus pulposus cells with in vivo disc model (NOTCH2/Hes1/Hey2); separately exosome isolation and PRAF2 co-expression in CRC","pmids":["31619270","31198409"],"confidence":"Medium","gaps":["Mechanism of PRAF2-dependent exosome loading not detailed","Non-canonical pathway receptor-independence not fully mapped"]},{"year":2021,"claim":"Identified JAG2 loss-of-function as a cause of human muscular dystrophy and placed it upstream of myogenic regulators including PAX7 and MEGF10.","evidence":"Whole-exome sequencing, patient muscle transcriptomics, Jag2 siRNA in myoblasts, Drosophila Serrate-Drpr genetic interaction","pmids":["33861953"],"confidence":"Medium","gaps":["Cellular source of the dystrophy-relevant signal not yet resolved","Receptor in muscle not identified at this stage"]},{"year":2022,"claim":"Defined post-translational control of JAG2 surface abundance by gamma-secretase and GSK3, tuning Notch signal strength to set airway epithelial fate.","evidence":"Human air-liquid-interface cultures with gamma-secretase inhibitors, GSK3/WNT modulators, biochemical fractionation, RNA-Seq","pmids":["35819850"],"confidence":"Medium","gaps":["Direct GSK3 phosphorylation site on JAG2 not mapped"]},{"year":2024,"claim":"Demonstrated ligand-specific JAG2/NOTCH1 control of sebocyte differentiation in vivo using selective antibody blockade with reversibility.","evidence":"Monoclonal antibody inhibition of individual Notch ligands/receptors in mouse skin, histology","pmids":["39585329"],"confidence":"High","gaps":["Transcriptional program downstream in sebocytes not detailed"]},{"year":2024,"claim":"Established the structural/regulatory basis distinguishing JAG2 from other ligands, showing it cannot be activated by NEURL proteins due to absence of the NxxN motif.","evidence":"Humanized Drosophila rescue and mammalian Notch activation assays with motif analysis (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Functional consequence of NEURL-independence in vivo not tested"]},{"year":2025,"claim":"Resolved the cell-autonomous logic of JAG2 in muscle, separating trans-activation of stem cell self-renewal from cis-inhibition of differentiation, and validated pathogenic variants as causal.","evidence":"MuEC- and MuSC-specific conditional knockout mice, co-culture, hypomorph model, Drosophila rescue with human variants","pmids":["42154534"],"confidence":"High","gaps":["Molecular determinants of cis vs trans bias not defined","Receptor identity in MuSC niche not specified"]},{"year":2025,"claim":"Expanded JAG2's oncogenic role into immune microenvironment remodeling, showing it acts through multiple Notch receptors to generate immunosuppressive T cell and macrophage states and to support stemness.","evidence":"JAG2 neutralizing antibodies and Notch inhibitors in co-culture, xenograft, organoid and single-cell studies across eTreg (NOTCH-RBPJ), macrophage (NOTCH3-STAT3-CCL2), and CD146-NF-κB-JAG2 axes","pmids":["40120139","41916520","40032820"],"confidence":"Medium","gaps":["Whether one or several receptors dominate per tumor context unclear","Single-lab axes await cross-validation"]},{"year":2025,"claim":"Added a deubiquitination layer to JAG2 regulation, with Usp11 stabilizing JAG2 to sustain marginal zone B cell survival.","evidence":"Co-immunoprecipitation, ubiquitination assay, Usp11 knockout mice, flow cytometry","pmids":["39904982"],"confidence":"Medium","gaps":["Ubiquitin ligase opposing Usp11 not identified","Specific JAG2 ubiquitination sites not mapped"]},{"year":null,"claim":"It remains unresolved how the choice between JAG2 cis-inhibition and trans-activation is molecularly controlled, and which Notch receptor pairs predominate across the many tissue and tumor contexts where JAG2 acts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of JAG2-receptor engagement in the corpus","Determinants of cis vs trans signaling undefined","Receptor usage in most tumor contexts not pinned down"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,18,24]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,13,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,13,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,15,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,22,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,21,25]}],"complexes":[],"partners":["NOTCH1","NOTCH2","NOTCH3","DLL1","USP11","PRAF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y219","full_name":"Protein jagged-2","aliases":[],"length_aa":1238,"mass_kda":133.4,"function":"Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y219/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JAG2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JAG2","total_profiled":1310},"omim":[{"mim_id":"619566","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 27; LGMDR27","url":"https://www.omim.org/entry/619566"},{"mim_id":"611141","title":"MIB E3 UBIQUITIN PROTEIN LIGASE 2; MIB2","url":"https://www.omim.org/entry/611141"},{"mim_id":"608582","title":"EPIDERMAL GROWTH FACTOR-LIKE 7; EGFL7","url":"https://www.omim.org/entry/608582"},{"mim_id":"608183","title":"CHONDROITIN SULFATE SYNTHASE 1; CHSY1","url":"https://www.omim.org/entry/608183"},{"mim_id":"607199","title":"INTERFERON REGULATORY FACTOR 6; IRF6","url":"https://www.omim.org/entry/607199"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Supernumerary hair cells in double mutants arise through cell fate switching rather than excess proliferation.\",\n      \"method\": \"Genetic epistasis (Dll1/Jag2 double mutant mice), conditional inactivation of Notch1\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis with double mutants and conditional receptor knockout, replicated across multiple allele combinations\",\n      \"pmids\": [\"16141228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"JAG2 (Jagged2) functions as a Notch ligand mediating lateral inhibition in cochlear development; loss of Jag2 leads to increased Math1-expressing cells and dramatically reduced HES5 expression in supporting cells, consistent with JAG2-activated Notch suppressing Math1 through HES5.\",\n      \"method\": \"In situ hybridization in wild-type vs. Jag2 mutant cochleae\",\n      \"journal\": \"Journal of the Association for Research in Otolaryngology : JARO\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular readouts (Math1, HES5) in a genetic model, single lab\",\n      \"pmids\": [\"11545143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"JAG2 is required for Notch1 activation in oral periderm cells during palatogenesis; Jag2 mutants show significantly attenuated Notch1 activation in oral epithelium and defective periderm differentiation, causing palate-tongue fusions. Recombinant explant cultures confirmed the Jag2 mutant tongue fuses to wild-type palatal shelves.\",\n      \"method\": \"Jag2 knockout mouse analysis, molecular marker analysis, recombinant explant co-culture\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model combined with ex vivo recombinant explant assay and molecular pathway validation (Notch1 activation)\",\n      \"pmids\": [\"16607638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAG2 overexpression in multiple myeloma malignant plasma cells induces IL-6, VEGF, and IGF-1 secretion from stromal cells in vitro; this IL-6 induction was blocked by anti-Notch-1 monoclonal antibodies targeting the Notch-1/JAG2 binding sequence, indicating JAG2 signals through NOTCH1. JAG2 overexpression is associated with hypomethylation of its promoter.\",\n      \"method\": \"In vitro co-culture assay, neutralizing antibody blocking experiment, promoter methylation analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-culture assay with pathway-specific antibody blockade, single lab\",\n      \"pmids\": [\"15292061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JAG2 promoter is aberrantly acetylated in multiple myeloma due to reduced levels of the SMRT corepressor, which normally recruits HDACs to the JAG2 promoter; restoration of SMRT function induced JAG2 downregulation and MM cell apoptosis.\",\n      \"method\": \"Chromatin acetylation analysis, SMRT overexpression/restoration, apoptosis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with defined epigenetic mechanism, single lab, multiple methods\",\n      \"pmids\": [\"19417136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DeltaNp63 transcription factor enhances Jag2 expression in thymic epithelial cells in vivo; p63-/- thymi show reduced Jag2 expression and reduced γδ T cell formation similar to Jag2-/- thymi, placing JAG2 downstream of DeltaNp63 in thymic development.\",\n      \"method\": \"Genetic complementation (p63-/- mice crossed with DeltaNp63α or TAp63α transgenic mice), in vivo gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via in vivo complementation, single lab\",\n      \"pmids\": [\"17626181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JAG2 is a direct transcriptional target of ectopic MYC in human B cells; JAG2 expression promotes hypoxic cell proliferation and in vivo tumorigenesis. RNAi targeting JAG2 or gamma-secretase inhibitor DAPT preferentially inhibited the neoplastic (Myc-high) state.\",\n      \"method\": \"Inducible Myc expression system (P493-6 cells), RNAi knockdown, gamma-secretase inhibitor treatment, in vivo xenograft assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Myc-inducible system with RNAi and pharmacological inhibition plus in vivo validation, single lab\",\n      \"pmids\": [\"20133585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAG2 is transcriptionally activated by hypoxia in a HIF-1α-dependent manner; hypoxic JAG2 induction increases NOTCH1 intracellular domain levels and HEY1 expression in tumor cells, and JAG2 siRNA knockdown in breast cancer cells reduces endothelial capillary tube formation in co-culture.\",\n      \"method\": \"HIF-1α siRNA knockdown, Notch target gene expression analysis (icN1, HEY1), JAG2 siRNA + endothelial co-culture tube formation assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HIF-1α-dependence established by knockdown, functional consequence shown in co-culture, single lab\",\n      \"pmids\": [\"21402725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JAG2 expression is required for clonogenic (self-renewal) growth of myeloma cells; silencing JAG2 blocked colony formation in vitro and in vivo tumor formation in immunocompromised mice. Blocking JAG-NOTCH interactions with NOTCH-Fc chimeric molecules also impaired colony formation.\",\n      \"method\": \"JAG2 siRNA knockdown, NOTCH-Fc chimeric molecule blocking, colony formation assay, in vivo xenograft\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function by RNAi and pathway blockade with in vivo confirmation, single lab\",\n      \"pmids\": [\"22341562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JAG2 promotes invasion, migration, and clonogenic growth in uveal melanoma cells; JAG2 overexpression increases Hes1 mRNA (a Notch target), and shRNA-mediated knockdown suppresses growth, invasion, and migration. JAG2 and Hes1 mRNA are enriched in invasive cells that pass through Matrigel.\",\n      \"method\": \"JAG2-GFP-MSCV overexpression, sh-JAG2 knockdown, transwell invasion/wound-healing assays, soft agar colony assay\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"23211831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BACE1 (β-secretase) does NOT effectively cleave JAG2, in contrast to its cleavage of JAG1, indicating selective protease-mediated regulation between these paralogs; JAG2 ectodomain shedding by BACE1 is absent despite high homology with JAG1.\",\n      \"method\": \"In vitro BACE1 cleavage assay, comparison between Jag1 and Jag2 substrates, BACE1-null mouse analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay directly comparing JAG1 vs JAG2 as substrates, single lab; finding is a negative result\",\n      \"pmids\": [\"24907271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JAG2 is a transcriptional target of MYC in medulloblastoma (Group 3/MYC-driven); MYC-induced transcriptional activation of JAG2 was identified as the mechanistic link between MYC oncogene activity and Notch pathway activation in MB cells.\",\n      \"method\": \"MYC knockdown/overexpression, qPCR, correlation analysis in primary tumor cohorts\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MYC-JAG2 transcriptional link shown by expression analysis and knockdown, corroborates Yustein 2010, single lab without direct promoter binding assay\",\n      \"pmids\": [\"24708907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JAG2 expression in colorectal cancer is regulated by Wnt/β-catenin signaling; pharmacological or genetic inhibition of β-catenin suppressed JAG2 expression, and APC deletion upregulated JAG2. JAG2 modulates chemoresistance through p21: JAG2 knockdown reduced p21, sensitizing cells to chemotherapy, and forced p21 expression rescued sensitivity; p21-null cells were unaffected by JAG2 knockdown.\",\n      \"method\": \"β-catenin inhibitors, β-catenin siRNA, APC conditional knockout mice, JAG2 knockdown/overexpression, p21 forced expression, chemosensitivity assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between JAG2 and p21 in chemoresistance established by rescue experiment; Wnt regulation confirmed by multiple methods, single lab\",\n      \"pmids\": [\"28881809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAG2 activates Notch2/Hes1/Hey2 signaling in nucleus pulposus (NP) cells to promote proliferation; this involves cyclin D1 regulation and activation of PI3K/Akt and Wnt/β-catenin pathways. JAG2/Notch2 signaling inhibits TNF-α-induced apoptosis by suppressing formation of the RIP1-FADD-caspase-8 complex. Intradiscal JAG2 injection alleviated intervertebral disc degeneration in rats.\",\n      \"method\": \"Recombinant JAG2 treatment, Notch2/Hes1/Hey2 siRNA, cell cycle analysis, PI3K/Akt and Wnt pathway assessment, apoptosis complex immunoprecipitation, in vivo rat disc injection model\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant ligand activation combined with siRNA pathway dissection and in vivo rescue, single lab\",\n      \"pmids\": [\"31619270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAG2 promotes migration and invasion of colorectal cancer cells through a non-canonical, Notch-independent and EMT-independent pathway. JAG2 co-expression with PRAF2 was identified; JAG2-rich exosomes are released from CRC cells in a PRAF2-dependent manner, and these exosomes promote metastasis in a paracrine fashion.\",\n      \"method\": \"siRNA knockdown, transcriptome microarray, exosome isolation and characterization, EMT pathway inhibitors, co-culture assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — JAG2-PRAF2 co-expression and exosome-mediated paracrine mechanism identified using multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"31198409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function JAG2 variants cause muscular dystrophy associated with misregulation of myogenesis genes including PAX7; Jag2 downregulation in murine myoblasts reduced multiple Notch pathway components including Megf10. Investigations in Drosophila revealed an interaction between Serrate (JAG1/JAG2 ortholog) and Drpr (MEGF10 ortholog), placing JAG2 upstream of MEGF10 in muscle development.\",\n      \"method\": \"Whole-exome sequencing, transcriptome analysis of patient muscle, Jag2 siRNA knockdown in murine myoblasts, Drosophila genetic interaction assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in multiple systems (human patient tissue, mouse myoblasts, Drosophila) with defined molecular phenotypes, single consortium\",\n      \"pmids\": [\"33861953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MSC secretome activates the IL-6-p-STAT3-p63-JAG2 pathway in lung basal cells; inhibition of IL-6/STAT3 signaling activates p63-JAG2 signaling, promoting p63+ cell proliferation and lung repair. This pathway placement was established in a bleomycin ALI mouse model.\",\n      \"method\": \"Bleomycin ALI mouse model, intratracheal MSC supernatant lyophilized powder treatment, western blot, immunofluorescence, flow cytometry, qPCR\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement (IL-6-STAT3-p63-JAG2) inferred from in vivo treatment model without direct JAG2 manipulation, single lab\",\n      \"pmids\": [\"33781349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAG1 and JAG2 undergo posttranslational modifications in tracheobronchial epithelium: gamma-secretase complex and glycogen synthase kinase 3 are implicated in generating a JAG1 C-terminal peptide and regulating full-length JAG2 abundance on the cell surface. These distinct assemblies of JAG1 and JAG2 regulate Notch signal strength and determine cell fate (goblet vs. ciliated cells).\",\n      \"method\": \"Human air-liquid-interface cultures, gamma-secretase inhibitors, neutralizing antibodies, WNT pathway antagonists/agonists, biochemical fractionation, RNA-Seq\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical evidence for posttranslational regulation of JAG2 surface abundance via GSC/GSK3, multiple pharmacological and molecular tools, single lab\",\n      \"pmids\": [\"35819850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JAG2/Notch1 is the primary signaling axis promoting sebocyte differentiation in homeostatic mouse skin; specific inhibition of JAG2 ligand (using monoclonal antibody) or Notch1 receptor causes loss of mature sebocytes and accumulation of proliferative progenitor cells. This phenotype is reversible upon removal of inhibition.\",\n      \"method\": \"Monoclonal antibody-mediated specific inhibition of individual Notch ligands/receptors in vivo (mouse), histological analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand-specific and receptor-specific antibody inhibition in vivo distinguishes JAG2/Notch1 axis from other ligand-receptor pairs, with reversibility control\",\n      \"pmids\": [\"39585329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NEURL1 and NEURL2 (Neuralized-like proteins) do NOT activate JAG2, because JAG2 lacks the Neuralized binding motif (consensus NxxN) present in DLL1 and JAG1 but absent in DLL4 and JAG2; this was demonstrated using humanized Drosophila and mammalian cell culture assays.\",\n      \"method\": \"Humanized Drosophila rescue assay, mammalian cell culture Notch activation assay, motif analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay in two systems showing NEURL proteins cannot activate JAG2; negative result with mechanistic basis (missing NxxN motif), preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Usp11 deubiquitinase sustains marginal zone B cell survival by deubiquitinating JAG2 (and DLL1), thereby maintaining Notch ligand levels; Usp11 knockout mice show increased MZ B cell survival after irradiation, and Co-IP/ubiquitination experiments confirmed the Usp11-JAG2 deubiquitination relationship.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Usp11 knockout mouse model, flow cytometry, immunofluorescence\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay establishing Usp11 as a deubiquitinase for JAG2, supported by in vivo KO model, single lab\",\n      \"pmids\": [\"39904982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JAG2+ tumor-associated neutrophils activate Notch signaling in CD4+ T cells via RBPJ-mediated transcription, driving their differentiation into effector regulatory T cells (eTregs); this was blocked by Notch inhibitor LY3039478 or JAG2 neutralizing antibodies. JAG2-NOTCH-RBPJ axis in macrophage-adjacent T cells was demonstrated by co-culture and in vivo xenograft models.\",\n      \"method\": \"In vitro co-culture, flow cytometry, Notch inhibitor LY3039478, JAG2 neutralizing antibodies, xenograft and patient-derived tumor organoid models, scRNA-seq\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — JAG2-Notch-RBPJ-eTreg axis established with pharmacological and antibody blockade plus in vivo models, single lab\",\n      \"pmids\": [\"40120139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD146 activates NF-κB signaling to upregulate JAG2 expression in hepatocellular carcinoma cells; JAG2 in turn activates Notch signaling to increase cancer stem cell stemness and chemoresistance. JAG2 overexpression rescued stemness and chemoresistance lost upon CD146 knockdown, placing JAG2 downstream of CD146-NF-κB.\",\n      \"method\": \"CD146 knockdown/overexpression, JAG2 overexpression rescue, NF-κB pathway analysis, in vitro stemness and chemoresistance assays, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiment placing JAG2 downstream of CD146-NF-κB, single lab\",\n      \"pmids\": [\"40032820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tumor-derived JAG2 signals through macrophage NOTCH3 to induce STAT3 phosphorylation and CCL2 upregulation in macrophages, promoting an immunosuppressive M2-like/neurotrophic phenotype that facilitates perineural invasion in colorectal cancer. Disruption of JAG2-NOTCH3 signaling, STAT3 inhibition, or CCL2 blockade attenuated these effects in vitro and in vivo.\",\n      \"method\": \"Single-cell transcriptomics, ligand-receptor interaction analysis, in vitro JAG2-NOTCH3 activation assays, STAT3 inhibition, CCL2 blockade, in vivo nerve invasion model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — JAG2-NOTCH3-STAT3-CCL2 axis established by multiple inhibition experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"41916520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JAG2 deficiency impairs Notch signaling in muscle stem cells (MuSCs) and disrupts myogenic self-renewal and differentiation. In cell-type-specific conditional knockout mice: MuEC-specific Jag2 knockout reduces MuSC self-renewal (trans-activation), while MuSC-specific Jag2 knockout reduces myogenic differentiation (cis-inhibition). Human pathogenic JAG2 variants, but not reference JAG2, fail to rescue Serrate (JAG2 Drosophila ortholog) deficiency, confirming variant-specific loss of function.\",\n      \"method\": \"Cell-type-specific conditional knockout mice (MuEC- and MuSC-specific), co-culture experiments, Jag2 hypomorphic mouse model, Drosophila rescue assay with pathogenic human JAG2 variants\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockouts distinguishing cis vs trans roles, cross-species rescue with pathogenic variants, multiple orthogonal models in single study\",\n      \"pmids\": [\"42154534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JAG2 signaling induces CD14+ monocytes to acquire an LCH (Langerhans cell histiocytosis)-like gene signature including CD1a and langerin expression; Notch inhibition suppresses the LCH phenotype, placing JAG2-mediated Notch activation as an initiating event in monocyte-to-LCH-like cell differentiation.\",\n      \"method\": \"JAG2-stimulated monocyte differentiation assay, gene expression profiling, Notch inhibitor treatment, flow cytometry\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — JAG2-Notch axis causally linked to monocyte differentiation phenotype using both activation and inhibition, single lab\",\n      \"pmids\": [\"30296338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JAG2 (Jagged2) is a canonical cell-surface Notch ligand that activates NOTCH1 and NOTCH2 receptors to regulate cell fate decisions in multiple tissues, including cochlear hair cell patterning via lateral inhibition, oral epithelial differentiation, sebaceous gland differentiation (Jag2/Notch1 axis), muscle stem cell self-renewal and differentiation (via cell-type-specific cis-inhibition and trans-activation), and immune cell fate; its expression is transcriptionally induced by MYC and HIF-1α, epigenetically regulated via SMRT-HDAC-dependent promoter acetylation, and its surface abundance is controlled post-translationally by gamma-secretase and glycogen synthase kinase 3, while Usp11 deubiquitinates JAG2 to stabilize it; unlike JAG1, JAG2 is not cleaved by BACE1 and lacks the NxxN Neuralized-binding motif, making it insensitive to NEURL-mediated activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JAG2 (Jagged2) is a cell-surface Notch ligand that drives cell-fate decisions across developing epithelia, muscle, and immune compartments by activating Notch receptors on neighboring cells [#0, #2, #18]. In the cochlea it cooperates with DLL1 to signal through NOTCH1 and enforce lateral inhibition, restricting hair cell fate by inducing HES5 and suppressing Math1 [#0, #1], and analogous JAG2/NOTCH1 lateral-inhibition logic patterns oral periderm during palatogenesis [#2] and sebocyte differentiation in skin [#18]. In muscle, cell-type-specific knockouts resolve a dual mode of action: JAG2 on muscle endothelial cells trans-activates muscle stem cell self-renewal, while JAG2 on the stem cells themselves cis-inhibits to permit differentiation, and pathogenic human JAG2 variants that fail to rescue the Drosophila ortholog cause muscular dystrophy with PAX7 and MEGF10 misregulation [#15, #24]. JAG2 also acts as an oncogenic Notch ligand: its transcription is induced by MYC [#6], HIF-1α under hypoxia [#7], Wnt/β-catenin [#12], CD146-NF-κB [#22], and DeltaNp63 [#5], and is epigenetically derepressed in multiple myeloma through loss of SMRT-HDAC-mediated promoter deacetylation [#4]; downstream it activates NOTCH1/NOTCH2/NOTCH3 to support tumor self-renewal, invasion, chemoresistance, and an immunosuppressive microenvironment via effects on T cells and macrophages [#8, #9, #13, #21, #23]. JAG2 surface abundance is controlled post-translationally by gamma-secretase and GSK3 [#17] and stabilized by the deubiquitinase Usp11 [#20]; unlike its paralog JAG1, JAG2 is not cleaved by BACE1 [#10] and lacks the NxxN motif required for NEURL-mediated activation [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established JAG2 as a functional Notch ligand mediating lateral inhibition during sensory development, defining its core role in restricting cell fate.\",\n      \"evidence\": \"In situ hybridization comparing wild-type and Jag2 mutant cochleae with Math1/HES5 readouts\",\n      \"pmids\": [\"11545143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the specific Notch receptor engaged\", \"Molecular link to HES5 inferred from expression, not direct receptor activation assay\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved which receptor JAG2 signals through and the cellular basis of its phenotype, showing JAG2/DLL1 act synergistically via NOTCH1 to switch fate rather than alter proliferation.\",\n      \"evidence\": \"Genetic epistasis with Dll1/Jag2 double mutant mice and conditional Notch1 inactivation\",\n      \"pmids\": [\"16141228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address contribution of NOTCH2/3 in other tissues\", \"Mechanism of ligand cooperation not biochemically defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended JAG2-NOTCH1 lateral inhibition to a second developmental context, palatogenesis, establishing its requirement for periderm differentiation.\",\n      \"evidence\": \"Jag2 knockout mouse analysis with recombinant explant co-culture and Notch1 activation markers\",\n      \"pmids\": [\"16607638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of periderm differentiation not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed JAG2 downstream of a transcription factor, DeltaNp63, in immune-organ development, beginning to define its upstream regulation.\",\n      \"evidence\": \"Genetic complementation of p63-/- mice with DeltaNp63α/TAp63α transgenes and in vivo expression analysis\",\n      \"pmids\": [\"17626181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of DeltaNp63 to the JAG2 promoter not shown\", \"γδ T cell defect linked correlatively\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified JAG2 as a direct MYC transcriptional target linking oncogene activity to Notch pathway activation and tumor growth.\",\n      \"evidence\": \"Inducible Myc system, JAG2 RNAi, gamma-secretase inhibitor DAPT, and xenograft assays\",\n      \"pmids\": [\"20133585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor identity in this context not pinned\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed JAG2 is a hypoxia/HIF-1α-induced ligand with pro-angiogenic consequences, connecting the tumor microenvironment to JAG2-Notch signaling.\",\n      \"evidence\": \"HIF-1α siRNA knockdown, icN1/HEY1 readouts, JAG2 siRNA endothelial tube-formation co-culture\",\n      \"pmids\": [\"21402725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-1α binding to JAG2 promoter not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a functional requirement for JAG2 in cancer self-renewal, showing it sustains clonogenic growth of myeloma cells.\",\n      \"evidence\": \"JAG2 siRNA, NOTCH-Fc chimeric blockade, colony formation, in vivo xenograft\",\n      \"pmids\": [\"22341562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor specificity not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Uncovered an epigenetic mechanism of aberrant JAG2 activation in myeloma via loss of SMRT-recruited HDAC activity at its promoter.\",\n      \"evidence\": \"Chromatin acetylation analysis, SMRT restoration, apoptosis assay\",\n      \"pmids\": [\"19417136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SMRT occupancy at JAG2 promoter inferred\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished JAG2 from its paralog JAG1 at the level of protease regulation, showing JAG2 resists BACE1-mediated shedding.\",\n      \"evidence\": \"In vitro BACE1 cleavage assay comparing JAG1 vs JAG2 plus BACE1-null mouse analysis\",\n      \"pmids\": [\"24907271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; functional consequence of resistance not tested\", \"Other shedding proteases not surveyed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked Wnt/β-catenin regulation of JAG2 to chemoresistance through a p21-dependent effector arm in colorectal cancer.\",\n      \"evidence\": \"β-catenin inhibitors/siRNA, APC conditional knockout, JAG2 and p21 manipulation, chemosensitivity assays\",\n      \"pmids\": [\"28881809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p21 effect requires canonical Notch signaling unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed both a canonical NOTCH2 anti-apoptotic/proliferative role and a non-canonical Notch-independent exosomal metastasis function for JAG2.\",\n      \"evidence\": \"Recombinant JAG2 and siRNA in nucleus pulposus cells with in vivo disc model (NOTCH2/Hes1/Hey2); separately exosome isolation and PRAF2 co-expression in CRC\",\n      \"pmids\": [\"31619270\", \"31198409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PRAF2-dependent exosome loading not detailed\", \"Non-canonical pathway receptor-independence not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified JAG2 loss-of-function as a cause of human muscular dystrophy and placed it upstream of myogenic regulators including PAX7 and MEGF10.\",\n      \"evidence\": \"Whole-exome sequencing, patient muscle transcriptomics, Jag2 siRNA in myoblasts, Drosophila Serrate-Drpr genetic interaction\",\n      \"pmids\": [\"33861953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular source of the dystrophy-relevant signal not yet resolved\", \"Receptor in muscle not identified at this stage\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined post-translational control of JAG2 surface abundance by gamma-secretase and GSK3, tuning Notch signal strength to set airway epithelial fate.\",\n      \"evidence\": \"Human air-liquid-interface cultures with gamma-secretase inhibitors, GSK3/WNT modulators, biochemical fractionation, RNA-Seq\",\n      \"pmids\": [\"35819850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GSK3 phosphorylation site on JAG2 not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated ligand-specific JAG2/NOTCH1 control of sebocyte differentiation in vivo using selective antibody blockade with reversibility.\",\n      \"evidence\": \"Monoclonal antibody inhibition of individual Notch ligands/receptors in mouse skin, histology\",\n      \"pmids\": [\"39585329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional program downstream in sebocytes not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the structural/regulatory basis distinguishing JAG2 from other ligands, showing it cannot be activated by NEURL proteins due to absence of the NxxN motif.\",\n      \"evidence\": \"Humanized Drosophila rescue and mammalian Notch activation assays with motif analysis (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Functional consequence of NEURL-independence in vivo not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the cell-autonomous logic of JAG2 in muscle, separating trans-activation of stem cell self-renewal from cis-inhibition of differentiation, and validated pathogenic variants as causal.\",\n      \"evidence\": \"MuEC- and MuSC-specific conditional knockout mice, co-culture, hypomorph model, Drosophila rescue with human variants\",\n      \"pmids\": [\"42154534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of cis vs trans bias not defined\", \"Receptor identity in MuSC niche not specified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded JAG2's oncogenic role into immune microenvironment remodeling, showing it acts through multiple Notch receptors to generate immunosuppressive T cell and macrophage states and to support stemness.\",\n      \"evidence\": \"JAG2 neutralizing antibodies and Notch inhibitors in co-culture, xenograft, organoid and single-cell studies across eTreg (NOTCH-RBPJ), macrophage (NOTCH3-STAT3-CCL2), and CD146-NF-κB-JAG2 axes\",\n      \"pmids\": [\"40120139\", \"41916520\", \"40032820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether one or several receptors dominate per tumor context unclear\", \"Single-lab axes await cross-validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a deubiquitination layer to JAG2 regulation, with Usp11 stabilizing JAG2 to sustain marginal zone B cell survival.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, Usp11 knockout mice, flow cytometry\",\n      \"pmids\": [\"39904982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase opposing Usp11 not identified\", \"Specific JAG2 ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the choice between JAG2 cis-inhibition and trans-activation is molecularly controlled, and which Notch receptor pairs predominate across the many tissue and tumor contexts where JAG2 acts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of JAG2-receptor engagement in the corpus\", \"Determinants of cis vs trans signaling undefined\", \"Receptor usage in most tumor contexts not pinned down\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 18, 24]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 13, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 13, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 15, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 22, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 21, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NOTCH1\", \"NOTCH2\", \"NOTCH3\", \"DLL1\", \"USP11\", \"PRAF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}