{"gene":"RGMB","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2005,"finding":"RGMB (DRAGON) is a GPI-anchored BMP co-receptor that directly binds BMP2 and BMP4 (but not BMP7 or other TGFβ ligands), associates with BMP type I receptors (ALK2, ALK3, ALK6) and type II receptors (ActRII and ActRIIB), and enhances BMP but not TGFβ signaling in a ligand-dependent manner reducible by Noggin; signaling is reduced by dominant-negative Smad1 and ALK3/6.","method":"Direct binding assays, co-immunoprecipitation with BMP receptors, dominant-negative receptor/Smad constructs, Noggin inhibition, Xenopus embryo overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (binding assays, co-IP, dominant-negative mutagenesis, in vivo Xenopus model) in a single rigorous study; replicated by RGMa paper same year","pmids":["15671031"],"is_preprint":false},{"year":2004,"finding":"DRAGON (RGMB) is a GPI-anchored membrane protein transcriptionally regulated by DRG11, co-expressed with DRG11 in embryonic DRG and spinal cord, promotes homophilic cell adhesion, and promotes adhesion of mouse DRG neurons whereas mRGM reduces it.","method":"Genomic binding strategy/promoter analysis, DRG11 null mutant expression analysis, neuronal cell adhesion assays, homophilic interaction assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple methods (promoter binding, null mutant, adhesion assay) but single lab","pmids":["14985445"],"is_preprint":false},{"year":2005,"finding":"DRAGON (RGMB) localizes to lipid rafts within the plasma membrane of reproductive cells and enhances BMP2/BMP4 signaling in reproductive cell lines (Ishikawa, HeLa, LβT2, MCF-7, JEG3); expression is dynamically regulated throughout the reproductive tract.","method":"Immunocytochemistry, sucrose gradient ultracentrifugation fractionation, BMP signaling reporter assays in reproductive cell lines","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct subcellular fractionation with functional signaling readout, single lab","pmids":["15890774"],"is_preprint":false},{"year":2010,"finding":"DRAGON (RGMB) localizes to apical surfaces of tubular epithelial cells in thick ascending limbs, distal convoluted tubules, and collecting ducts; in mIMCD3 cells it enhances BMP signaling in a ligand-dependent manner using BMP4 as the predominant endogenous ligand, redirecting signaling through ActRIIA (rather than BMPRII) and increasing transepithelial resistance via the Smad1/5/8 pathway.","method":"Immunohistochemistry/localization in mouse kidney, BMP signaling assays in mIMCD3 cells, receptor knockdown, transepithelial resistance measurement","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with functional consequence, receptor-specific signaling demonstrated, multiple cell types tested","pmids":["20167703"],"is_preprint":false},{"year":2010,"finding":"DRAGON (RGMB) negatively regulates IL-6 expression in macrophages in a BMP ligand-dependent manner via the p38 MAPK and Erk1/2 pathways (not the Smad1/5/8 pathway); Dragon knockout mice show upregulated IL-6 in lung macrophages and dendritic cells.","method":"RAW264.7/J774 macrophage cell line assays, Dragon knockout mice, pathway inhibitor experiments, cytokine measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype, pathway dissection by multiple inhibitors, in vitro and in vivo","pmids":["21187450"],"is_preprint":false},{"year":2011,"finding":"RGMB (RGMb) promotes neurite outgrowth and peripheral nerve regeneration as a BMP co-receptor; RGMb knockout DRG neurons exhibit fewer and shorter neurites than wild-type, rescuable by BMP-2; RGMb deletion or BMP inhibition with Noggin retards early axonal regeneration after sciatic nerve crush in vivo.","method":"RGMb knockout mice, DRG explant and dissociated neuron culture, BMP-2 rescue, Noggin inhibition, sciatic nerve crush model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific cellular and in vivo phenotypic readouts, BMP-2 rescue experiment, multiple orthogonal assays","pmids":["22171041"],"is_preprint":false},{"year":2013,"finding":"DRAGON (RGMB) inhibits E-cadherin expression and induces apoptosis in renal tubular epithelial cells through the neogenin receptor (not the BMP pathway); Dragon overexpression increases hypoxia-induced cell death with elevated cleaved caspase-3 and PARP; heterozygous Dragon knockout mice show decreased tubular apoptosis and increased E-cadherin after ureteral obstruction.","method":"IMCD3 cell overexpression, neogenin knockdown, caspase/PARP cleavage assays, unilateral ureteral obstruction mouse model, heterozygous knockout mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in vivo, receptor-specific pathway dissection, multiple orthogonal assays in vitro and in vivo","pmids":["24052264"],"is_preprint":false},{"year":2014,"finding":"RGMB (RGMb) is a novel binding partner for PD-L2 (B7-DC); PD-L2 and BMP-2/4 bind to distinct sites on RGMb; blockade of the RGMb–PD-L2 interaction impairs respiratory tolerance by disrupting initial T cell expansion; PD-L2 expression on non-T cells (not T cells) is required for this tolerance.","method":"Binding assays identifying RGMb–PD-L2 interaction, PD-L2-deficient mice, anti-RGMb/anti-PD-L2 blockade in respiratory tolerance models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assays with site-mapping, genetic knockouts, in vivo functional tolerance model","pmids":["24752301"],"is_preprint":false},{"year":2009,"finding":"RGMb interacts physically with Neogenin (co-immunoprecipitation and binding assays) and controls aggregation and migration of Neogenin-positive dentate gyrus precursor cells; RGMb expression in structures bordering the developing dentate abolishes in vitro and in vivo migration of dentate neuroepithelial cells expressing Neogenin; ectopic RGMb in organotypic slice cultures modifies precursor cell migration.","method":"Co-immunoprecipitation, binding assays, organotypic slice cultures, in utero electroporation, in vitro migration assays","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays plus in vitro and in vivo migration phenotype, multiple approaches","pmids":["19944164"],"is_preprint":false},{"year":2009,"finding":"In C2C12 myoblasts, DRAGON (RGMB) suppresses BMP signaling (ALP and Id1 promoter activities induced by BMP-4 or constitutively active BMP type I receptors) via a novel mechanism dependent on the secretory form of the von Willebrand factor type D domain; this inhibition occurs even downstream of Smad1 activation and is not altered by neogenin overexpression.","method":"C2C12 myoblast reporter assays, domain deletion/mutant constructs, constitutively active receptor constructs, neogenin overexpression","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mutagenesis, multiple BMP signaling readouts, single lab","pmids":["19422419"],"is_preprint":false},{"year":2016,"finding":"RGMB (DRAGON) controls the balance of olfactory receptor neurons and sustentacular (glial-like) cells in the developing olfactory epithelium through interaction with neogenin; RGMB is expressed in newly born ORNs adjacent to neogenin-expressing progenitors; Rgmb ablation increases dividing progenitors and supernumerary SUS cells, phenocopied by neogenin loss-of-function.","method":"Gene-targeted Rgmb and Neo1 knockout mice, cell counting, BrdU incorporation, in situ hybridization, immunofluorescence","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genetic knockouts with specific quantitative cellular phenotypes, epistasis between RGMB and neogenin established","pmids":["27143755"],"is_preprint":false},{"year":2017,"finding":"PD-L2 (B7-DC) K113S mutant (which cannot bind PD-1) retains RGMb binding with similar affinity to wild-type PD-L2, costimulates CD4+ T cells via RGMb and promotes Th1 polarization; RGMb is expressed on naive mouse T cells, macrophages, neutrophils, and dendritic cells; K113S/RGMb costimulation suppresses Th2-mediated asthma in vivo.","method":"Binding affinity assays, T cell co-stimulation assays, Th1/Th2 polarization assays, murine allergic asthma model","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — binding and functional assays with PD-L2 mutant, in vivo disease model, single lab","pmids":["28479601"],"is_preprint":false},{"year":2018,"finding":"RGMb protects against acute kidney injury (ischemia/reperfusion and oxalate nephropathy) by reducing membrane-associated MLKL levels and inhibiting necroptosis in proximal tubular cells; tubule-specific Rgmb conditional knockout increases MLKL at the apical membrane of proximal tubular cells and worsens renal dysfunction; necroptosis inhibitors (Necrostatin-1, GSK'963) ameliorate injury in both wild-type and Rgmb cKO mice.","method":"Conditional tubular Rgmb knockout mice, ischemia/reperfusion and oxalate nephropathy models, MLKL membrane fractionation, necroptosis inhibitor treatment, renal function assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout with specific molecular (MLKL) and functional (renal dysfunction) readouts, pharmacological rescue, in vivo","pmids":["29382757"],"is_preprint":false},{"year":2019,"finding":"RGMB is a novel binding partner of CTLA-4; RGMB specifically strengthens binding of the monomeric soluble form of CTLA-4 (sCTLA-4) to CD80, thereby enhancing CTLA-4's suppressive effect on co-stimulation; RGMB is expressed at high levels in tolerogenic dendritic cell subsets.","method":"Pulldown/binding assays, co-stimulation suppression assays, CD80 binding enhancement assay, expression profiling of DC subsets","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding and functional co-stimulation assays, single lab, mechanistic follow-up limited","pmids":["31061392"],"is_preprint":false},{"year":2019,"finding":"Blockade of RGMb with anti-RGMb mAb effectively blocks development of airway inflammation and airway hyperreactivity in ovalbumin and cockroach allergen murine asthma models; RGMb is expressed on bronchial epithelial cells, activated eosinophils, and interstitial macrophages; neogenin (canonical RGMb receptor) is expressed by interstitial macrophages and bronchial epithelial cells in inflamed lung; IL-25 pathway is required for the disease.","method":"Anti-RGMb mAb treatment in murine asthma models, IL-25 receptor-deficient mice, immunostaining for RGMb and neogenin","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — antibody blockade with defined phenotypic readout, genetic KO of IL-25R for epistasis, single lab","pmids":["30703386"],"is_preprint":false},{"year":2012,"finding":"RGMB knockdown in breast cancer cells enhances proliferation, adhesion, and migration; mechanistically, knockdown reduces Caspase-3 expression/activity (improving survival under serum starvation) via repression of the MAPK JNK pathway, and increases Snai1, Twist, FAK, and Paxillin expression via enhanced Smad-dependent signaling.","method":"Ribozyme transgene knockdown of RGMB in breast cancer cells, proliferation/adhesion/migration assays, caspase activity assays, Western blotting for signaling molecules","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with multiple pathway readouts, single lab","pmids":["22415859"],"is_preprint":false},{"year":2015,"finding":"Dragon (RGMB) promotes colorectal cancer cell proliferation and tumor growth via BMP4-Smad1/5/8 and Erk1/2 pathways; Dragon expression is elevated in colon cancer tissues in mouse CAC model and human patients.","method":"RGMB overexpression in CT26.WT and CMT93 cells, xenograft mouse model, BMP4-Smad1/5/8 and Erk1/2 pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function with in vitro and in vivo tumor readouts, pathway analysis, single lab","pmids":["26029998"],"is_preprint":false},{"year":2016,"finding":"Dragon (RGMB) induces resistance to oxaliplatin in colon cancer cells by inhibiting oxaliplatin-induced JNK and p38 MAPK activation and blocking caspase-3 and PARP cleavage; Dragon-expressing xenograft tumors show reduced response to oxaliplatin.","method":"Dragon overexpression in CMT93/HCT116 cells, oxaliplatin treatment, apoptosis assays, JNK/p38 MAPK pathway analysis, xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function with pharmacological challenge, pathway readouts, in vivo xenograft, single lab","pmids":["27384995"],"is_preprint":false},{"year":2022,"finding":"RNF4 ubiquitin ligase promotes osteogenic differentiation of hBMSCs by transcriptionally upregulating both RGMb and BMP6; knockdown of either RGMb or BMP6 halts osteogenic differentiation; combined addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restores osteogenic differentiation, placing RGMb downstream of RNF4 in an RNF4–RGMb–BMP6 axis required for osteogenesis and osteosarcoma cell survival.","method":"RNF4/RGMb/BMP6 knockdown in hBMSCs, conditioned media rescue, purified protein add-back, osteosarcoma cell survival assays, transcriptional analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (knockdown of each component), purified protein reconstitution rescue, multiple orthogonal assays, single lab","pmids":["36153321"],"is_preprint":false},{"year":2022,"finding":"Human sensory neurons secrete RGMB protein, which induces morphogenesis and melanin production in human melanocytes; RGMB was identified in sensory neuron-conditioned medium by proteomic analysis; transcriptome analysis indicates RGMB controls the melanosome transport machinery.","method":"Proteomic analysis of conditioned medium, co-culture of iPSC-derived sensory neurons with melanocytes, RGMB protein treatment of melanocytes, transcriptome analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification, direct protein treatment with functional readout, transcriptomic follow-up, single lab","pmids":["36130522"],"is_preprint":false},{"year":2023,"finding":"The gut microbiome downregulates PD-L2 and its binding partner RGMb to promote anti-tumor immunity; antibody-mediated blockade of the PD-L2–RGMb pathway, or conditional deletion of RGMb in T cells, combined with anti-PD-1 or anti-PD-L1 overcomes microbiome-dependent resistance to checkpoint inhibitors in multiple mouse tumor models including germ-free, antibiotic-treated, and non-responder stool-colonized mice.","method":"Conditional T cell-specific RGMb knockout mice, anti-PD-L2/anti-RGMb antibody blockade, multiple syngeneic tumor models, germ-free and antibiotic-treated mouse experiments, fecal transplant experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout plus antibody blockade, multiple independent tumor models, microbiome manipulation, replicated across experimental conditions","pmids":["37138075"],"is_preprint":false}],"current_model":"RGMB (DRAGON) is a GPI-anchored membrane protein that functions as a BMP co-receptor by directly binding BMP2/4 and associating with type I and type II BMP receptors to potentiate Smad1/5/8 and MAPK signaling; it also acts as a ligand for the neogenin receptor to control cell migration, neuronal/glial differentiation, and epithelial apoptosis independently of BMP; in the immune system it serves as a binding partner for both PD-L2 (regulating respiratory tolerance and anti-tumor immunity) and CTLA-4 (modulating co-stimulation), and in the kidney it suppresses MLKL-dependent necroptosis to protect against acute injury."},"narrative":{"mechanistic_narrative":"RGMB (DRAGON) is a GPI-anchored cell-surface protein that operates at the intersection of BMP signaling, neogenin-dependent guidance, and immune co-regulation [PMID:15671031, PMID:19944164, PMID:37138075]. As a BMP co-receptor it directly binds BMP2 and BMP4 — but not BMP7 or other TGFβ ligands — associates with type I (ALK2/3/6) and type II (ActRII/ActRIIB) BMP receptors, and potentiates ligand-dependent Smad1/5/8 signaling in a manner blocked by Noggin and dominant-negative Smad1/ALK3/6 [PMID:15671031]; it localizes to lipid rafts and apical epithelial surfaces and can redirect signaling through ActRIIA to modulate epithelial barrier function [PMID:15890774, PMID:20167703]. Beyond Smads, RGMB engages the p38/Erk MAPK arm to negatively regulate macrophage IL-6 [PMID:21187450], and in some contexts suppresses BMP output via its von Willebrand factor type D domain independently of neogenin [PMID:19422419]. Independently of BMP, RGMB acts as a ligand for the neogenin receptor to control precursor cell aggregation, migration, and neuron-versus-glia fate decisions in the developing nervous system [PMID:19944164, PMID:27143755], and through neogenin it drives E-cadherin loss and caspase-dependent apoptosis in renal tubular epithelium [PMID:24052264]. In the immune system RGMB is a binding partner for PD-L2 — at a site distinct from the BMP-binding site — controlling respiratory tolerance, T cell co-stimulation, and microbiome-dependent anti-tumor immunity, such that blockade or T-cell-specific deletion of RGMB overcomes resistance to PD-1/PD-L1 checkpoint inhibition [PMID:24752301, PMID:28479601, PMID:37138075]; it also binds CTLA-4 to strengthen sCTLA-4 engagement of CD80 [PMID:31061392]. In the kidney, RGMB protects against acute injury by limiting membrane-associated MLKL and inhibiting necroptosis in proximal tubular cells [PMID:29382757]. RGMB further functions as a secreted regulator of melanocyte morphogenesis and an RNF4-induced effector required for osteogenic differentiation via an RNF4–RGMB–BMP6 axis [PMID:36153321, PMID:36130522].","teleology":[{"year":2004,"claim":"Establishing RGMB's first molecular identity, it was defined as a GPI-anchored, DRG11-regulated adhesion molecule, setting it as a sensory-system membrane protein before any signaling role was known.","evidence":"Promoter/genomic binding analysis, DRG11-null expression analysis, and homophilic adhesion assays in DRG neurons","pmids":["14985445"],"confidence":"Medium","gaps":["No receptor partner identified at this stage","Adhesion mechanism and binding partners undefined"]},{"year":2005,"claim":"The central biochemical function was resolved by showing RGMB is a BMP co-receptor that selectively binds BMP2/4 and associates with type I/II BMP receptors to amplify Smad1/5/8 signaling.","evidence":"Direct binding/co-IP with BMP receptors, dominant-negative Smad1/ALK3/6, Noggin inhibition, and Xenopus overexpression","pmids":["15671031","15890774"],"confidence":"High","gaps":["Structural basis of ligand selectivity not resolved","How GPI-anchoring couples to receptor complex assembly unclear"]},{"year":2009,"claim":"RGMB was shown to act as a neogenin ligand controlling precursor migration, establishing a BMP-independent signaling axis, while a separate study showed it can also suppress BMP output through its vWF type D domain.","evidence":"Reciprocal co-IP/binding with neogenin plus organotypic slice and in utero migration assays; domain-deletion reporter assays in C2C12 myoblasts","pmids":["19944164","19422419"],"confidence":"High","gaps":["Context determining co-receptor potentiation versus suppression unresolved","Downstream neogenin effectors in migration not mapped"]},{"year":2010,"claim":"Tissue-specific signaling outputs were defined, showing RGMB enhances Smad-dependent barrier function in kidney epithelium via ActRIIA and negatively regulates macrophage IL-6 through MAPK rather than Smad.","evidence":"Kidney immunolocalization and mIMCD3 receptor-knockdown/transepithelial resistance assays; macrophage cell lines, Dragon-knockout mice, and MAPK inhibitor dissection","pmids":["20167703","21187450"],"confidence":"High","gaps":["Mechanism of receptor switching to ActRIIA unknown","How RGMB selects Smad versus MAPK output not defined"]},{"year":2011,"claim":"Genetic loss-of-function established a physiological developmental requirement, with RGMb promoting BMP-2-dependent neurite outgrowth and peripheral nerve regeneration.","evidence":"RGMb knockout DRG neuron cultures with BMP-2 rescue and in vivo sciatic nerve crush","pmids":["22171041"],"confidence":"High","gaps":["Receptor complex mediating regenerative effect not specified","Relative contribution of BMP versus neogenin in regeneration unresolved"]},{"year":2013,"claim":"A pro-apoptotic, neogenin-dependent role was demonstrated, expanding RGMB beyond a growth-promoting co-receptor to a driver of epithelial cell death and E-cadherin loss in injured kidney.","evidence":"IMCD3 overexpression with neogenin knockdown, caspase/PARP assays, and ureteral obstruction in heterozygous knockout mice","pmids":["24052264"],"confidence":"High","gaps":["Signaling linking neogenin to caspase activation not delineated","Reconciliation with protective renal roles unclear"]},{"year":2014,"claim":"RGMB was identified as a PD-L2 binding partner with a distinct binding site from BMP, defining a new immune-checkpoint-adjacent function in respiratory tolerance.","evidence":"Binding assays with site-mapping, PD-L2-deficient mice, and anti-RGMb/anti-PD-L2 blockade in respiratory tolerance models","pmids":["24752301"],"confidence":"High","gaps":["Intracellular signaling triggered by RGMb–PD-L2 engagement undefined","Cell-type-specific outputs of the interaction not fully resolved"]},{"year":2017,"claim":"The PD-L2–RGMb axis was shown to be PD-1-independent and co-stimulatory, with PD-L2 driving Th1 polarization and suppressing Th2 asthma via RGMb.","evidence":"PD-L2 K113S mutant binding/co-stimulation assays, Th1/Th2 polarization, and murine allergic asthma model","pmids":["28479601"],"confidence":"Medium","gaps":["RGMb-proximal signaling in T cell co-stimulation not mapped","Single lab, requires independent confirmation"]},{"year":2018,"claim":"A cytoprotective mechanism distinct from its pro-apoptotic role was defined, with RGMb limiting membrane MLKL to inhibit necroptosis and protect tubular cells in acute kidney injury.","evidence":"Tubule-specific conditional Rgmb knockout in ischemia/reperfusion and oxalate nephropathy, MLKL membrane fractionation, and necroptosis-inhibitor rescue","pmids":["29382757"],"confidence":"High","gaps":["Molecular link between RGMb and MLKL regulation unknown","Whether this is BMP- or neogenin-dependent not established"]},{"year":2019,"claim":"RGMB's immune-modulatory repertoire was broadened by identifying it as a CTLA-4 binding partner that strengthens sCTLA-4–CD80 engagement, and by showing anti-RGMb blockade suppresses allergic airway disease.","evidence":"Pulldown/binding and co-stimulation suppression assays with CD80; anti-RGMb mAb in ovalbumin/cockroach asthma models with IL-25R-deficient mice","pmids":["31061392","30703386"],"confidence":"Medium","gaps":["Structural basis of CTLA-4 interaction not resolved","Receptor mediating RGMb effects in airway inflammation not pinned down"]},{"year":2022,"claim":"Two new effector functions were established: RGMB as a secreted regulator of melanocyte morphogenesis/melanin and as an RNF4-induced node in an RNF4–RGMB–BMP6 osteogenic axis.","evidence":"Proteomic identification from sensory neuron-conditioned medium with melanocyte treatment; RNF4/RGMb/BMP6 knockdown and purified-protein add-back rescue in hBMSCs","pmids":["36130522","36153321"],"confidence":"High","gaps":["Melanocyte receptor for secreted RGMB unidentified","How RNF4 transcriptionally controls RGMB not detailed"]},{"year":2023,"claim":"The therapeutic significance of the RGMb–PD-L2 axis was established, showing the gut microbiome regulates this pathway and that blocking or deleting RGMb in T cells overcomes microbiome-dependent checkpoint-inhibitor resistance.","evidence":"T-cell-specific conditional Rgmb knockout, anti-RGMb/anti-PD-L2 blockade across syngeneic tumor models, and germ-free/antibiotic/fecal-transplant experiments","pmids":["37138075"],"confidence":"High","gaps":["Intracellular signaling downstream of RGMb in T cells unresolved","Microbiome-to-RGMb regulatory mechanism not fully defined"]},{"year":null,"claim":"How a single GPI-anchored protein integrates BMP co-receptor signaling, neogenin ligand activity, and PD-L2/CTLA-4 immune binding into context-specific outputs — and the structural and intracellular basis of each — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of RGMB's multiple binding interfaces","Determinants selecting Smad versus MAPK versus neogenin output unknown","Proximal intracellular signaling of GPI-anchored RGMB undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[8,10,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9,13]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,13,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,10,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,12]}],"complexes":[],"partners":["BMP2","BMP4","ALK3","ACTRIIA","NEO1","PDCD1LG2","CTLA4","BMP6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NW40","full_name":"Repulsive guidance molecule B","aliases":["DRG11-responsive axonal guidance and outgrowth of neurite","DRAGON"],"length_aa":437,"mass_kda":47.5,"function":"Member of the repulsive guidance molecule (RGM) family that contributes to the patterning of the developing nervous system (By similarity). Acts as a bone morphogenetic protein (BMP) coreceptor that potentiates BMP signaling (By similarity). Promotes neuronal adhesion (By similarity). May inhibit neurite outgrowth","subcellular_location":"Cell membrane; Membrane raft","url":"https://www.uniprot.org/uniprotkb/Q6NW40/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RGMB","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RGMB","total_profiled":1310},"omim":[{"mim_id":"617682","title":"PILAROWSKI-BJORNSSON SYNDROME; PILBOS","url":"https://www.omim.org/entry/617682"},{"mim_id":"612687","title":"RGM DOMAIN FAMILY, MEMBER B; RGMB","url":"https://www.omim.org/entry/612687"},{"mim_id":"602118","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 1; CHD1","url":"https://www.omim.org/entry/602118"},{"mim_id":"601907","title":"NEOGENIN; NEO1","url":"https://www.omim.org/entry/601907"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RGMB"},"hgnc":{"alias_symbol":["FLJ90406","DRAGON"],"prev_symbol":[]},"alphafold":{"accession":"Q6NW40","domains":[{"cath_id":"3.40.1000.10","chopping":"161-319","consensus_level":"medium","plddt":94.1207,"start":161,"end":319},{"cath_id":"1.20.58","chopping":"56-120","consensus_level":"high","plddt":91.4389,"start":56,"end":120},{"cath_id":"1.10.8","chopping":"329-334_345-405","consensus_level":"medium","plddt":85.8045,"start":329,"end":405}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NW40","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NW40-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NW40-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RGMB","jax_strain_url":"https://www.jax.org/strain/search?query=RGMB"},"sequence":{"accession":"Q6NW40","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NW40.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NW40/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NW40"}},"corpus_meta":[{"pmid":"24752301","id":"PMC_24752301","title":"RGMb 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Renal Asian Genetics Network (DRAGoN).","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35064937","citation_count":12,"is_preprint":false},{"pmid":"23073896","id":"PMC_23073896","title":"RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis.","date":"2012","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/23073896","citation_count":11,"is_preprint":false},{"pmid":"37579915","id":"PMC_37579915","title":"DRAGON: Harnessing the power of DNA repair for accelerating genome evolution in Corynebacterium glutamicum.","date":"2023","source":"Metabolic engineering","url":"https://pubmed.ncbi.nlm.nih.gov/37579915","citation_count":11,"is_preprint":false},{"pmid":"29710804","id":"PMC_29710804","title":"Proteomic and Biochemical Changes during Senescence of Phalaenopsis 'Red Dragon' Petals.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29710804","citation_count":11,"is_preprint":false},{"pmid":"35110618","id":"PMC_35110618","title":"In vitro regeneration and Agrobacterium-mediated genetic transformation of Dragon's Head plant (Lallemantia iberica).","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35110618","citation_count":10,"is_preprint":false},{"pmid":"32092837","id":"PMC_32092837","title":"Dragon's Blood Inhibits Chronic Inflammatory and Neuropathic Pain Responses by Blocking the Synthesis and Release of Substance P in Rats.","date":"2019","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32092837","citation_count":10,"is_preprint":false},{"pmid":"30641525","id":"PMC_30641525","title":"Isolating Chromosomes of the Komodo Dragon: New Tools for Comparative Mapping and Sequence Assembly.","date":"2019","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/30641525","citation_count":10,"is_preprint":false},{"pmid":"34583851","id":"PMC_34583851","title":"LncRNA RGMB-AS1 up-regulates ANKRD1 Through Competitively Sponging miR-3614-5p to Promote OSA Cell Proliferation and Invasion.","date":"2021","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/34583851","citation_count":9,"is_preprint":false},{"pmid":"34751624","id":"PMC_34751624","title":"Curcumin mediates repulsive guidance molecule B (RGMb) in the treatment mechanism of renal fibrosis induced by unilateral ureteral obstruction.","date":"2021","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/34751624","citation_count":9,"is_preprint":false},{"pmid":"33082398","id":"PMC_33082398","title":"MicroRNA dynamics during hibernation of the Australian central bearded dragon (Pogona vitticeps).","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33082398","citation_count":9,"is_preprint":false},{"pmid":"33521854","id":"PMC_33521854","title":"A botanical medicine dragon's blood exhibited clinical antithrombosis efficacy similar to low molecular weight heparin.","date":"2021","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33521854","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49119,"output_tokens":5467,"usd":0.114681,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13936,"output_tokens":4431,"usd":0.090228,"stage2_stop_reason":"end_turn"},"total_usd":0.204909,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"RGMB (DRAGON) is a GPI-anchored BMP co-receptor that directly binds BMP2 and BMP4 (but not BMP7 or other TGFβ ligands), associates with BMP type I receptors (ALK2, ALK3, ALK6) and type II receptors (ActRII and ActRIIB), and enhances BMP but not TGFβ signaling in a ligand-dependent manner reducible by Noggin; signaling is reduced by dominant-negative Smad1 and ALK3/6.\",\n      \"method\": \"Direct binding assays, co-immunoprecipitation with BMP receptors, dominant-negative receptor/Smad constructs, Noggin inhibition, Xenopus embryo overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (binding assays, co-IP, dominant-negative mutagenesis, in vivo Xenopus model) in a single rigorous study; replicated by RGMa paper same year\",\n      \"pmids\": [\"15671031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DRAGON (RGMB) is a GPI-anchored membrane protein transcriptionally regulated by DRG11, co-expressed with DRG11 in embryonic DRG and spinal cord, promotes homophilic cell adhesion, and promotes adhesion of mouse DRG neurons whereas mRGM reduces it.\",\n      \"method\": \"Genomic binding strategy/promoter analysis, DRG11 null mutant expression analysis, neuronal cell adhesion assays, homophilic interaction assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple methods (promoter binding, null mutant, adhesion assay) but single lab\",\n      \"pmids\": [\"14985445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DRAGON (RGMB) localizes to lipid rafts within the plasma membrane of reproductive cells and enhances BMP2/BMP4 signaling in reproductive cell lines (Ishikawa, HeLa, LβT2, MCF-7, JEG3); expression is dynamically regulated throughout the reproductive tract.\",\n      \"method\": \"Immunocytochemistry, sucrose gradient ultracentrifugation fractionation, BMP signaling reporter assays in reproductive cell lines\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct subcellular fractionation with functional signaling readout, single lab\",\n      \"pmids\": [\"15890774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DRAGON (RGMB) localizes to apical surfaces of tubular epithelial cells in thick ascending limbs, distal convoluted tubules, and collecting ducts; in mIMCD3 cells it enhances BMP signaling in a ligand-dependent manner using BMP4 as the predominant endogenous ligand, redirecting signaling through ActRIIA (rather than BMPRII) and increasing transepithelial resistance via the Smad1/5/8 pathway.\",\n      \"method\": \"Immunohistochemistry/localization in mouse kidney, BMP signaling assays in mIMCD3 cells, receptor knockdown, transepithelial resistance measurement\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with functional consequence, receptor-specific signaling demonstrated, multiple cell types tested\",\n      \"pmids\": [\"20167703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DRAGON (RGMB) negatively regulates IL-6 expression in macrophages in a BMP ligand-dependent manner via the p38 MAPK and Erk1/2 pathways (not the Smad1/5/8 pathway); Dragon knockout mice show upregulated IL-6 in lung macrophages and dendritic cells.\",\n      \"method\": \"RAW264.7/J774 macrophage cell line assays, Dragon knockout mice, pathway inhibitor experiments, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype, pathway dissection by multiple inhibitors, in vitro and in vivo\",\n      \"pmids\": [\"21187450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RGMB (RGMb) promotes neurite outgrowth and peripheral nerve regeneration as a BMP co-receptor; RGMb knockout DRG neurons exhibit fewer and shorter neurites than wild-type, rescuable by BMP-2; RGMb deletion or BMP inhibition with Noggin retards early axonal regeneration after sciatic nerve crush in vivo.\",\n      \"method\": \"RGMb knockout mice, DRG explant and dissociated neuron culture, BMP-2 rescue, Noggin inhibition, sciatic nerve crush model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific cellular and in vivo phenotypic readouts, BMP-2 rescue experiment, multiple orthogonal assays\",\n      \"pmids\": [\"22171041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DRAGON (RGMB) inhibits E-cadherin expression and induces apoptosis in renal tubular epithelial cells through the neogenin receptor (not the BMP pathway); Dragon overexpression increases hypoxia-induced cell death with elevated cleaved caspase-3 and PARP; heterozygous Dragon knockout mice show decreased tubular apoptosis and increased E-cadherin after ureteral obstruction.\",\n      \"method\": \"IMCD3 cell overexpression, neogenin knockdown, caspase/PARP cleavage assays, unilateral ureteral obstruction mouse model, heterozygous knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in vivo, receptor-specific pathway dissection, multiple orthogonal assays in vitro and in vivo\",\n      \"pmids\": [\"24052264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RGMB (RGMb) is a novel binding partner for PD-L2 (B7-DC); PD-L2 and BMP-2/4 bind to distinct sites on RGMb; blockade of the RGMb–PD-L2 interaction impairs respiratory tolerance by disrupting initial T cell expansion; PD-L2 expression on non-T cells (not T cells) is required for this tolerance.\",\n      \"method\": \"Binding assays identifying RGMb–PD-L2 interaction, PD-L2-deficient mice, anti-RGMb/anti-PD-L2 blockade in respiratory tolerance models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assays with site-mapping, genetic knockouts, in vivo functional tolerance model\",\n      \"pmids\": [\"24752301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RGMb interacts physically with Neogenin (co-immunoprecipitation and binding assays) and controls aggregation and migration of Neogenin-positive dentate gyrus precursor cells; RGMb expression in structures bordering the developing dentate abolishes in vitro and in vivo migration of dentate neuroepithelial cells expressing Neogenin; ectopic RGMb in organotypic slice cultures modifies precursor cell migration.\",\n      \"method\": \"Co-immunoprecipitation, binding assays, organotypic slice cultures, in utero electroporation, in vitro migration assays\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays plus in vitro and in vivo migration phenotype, multiple approaches\",\n      \"pmids\": [\"19944164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In C2C12 myoblasts, DRAGON (RGMB) suppresses BMP signaling (ALP and Id1 promoter activities induced by BMP-4 or constitutively active BMP type I receptors) via a novel mechanism dependent on the secretory form of the von Willebrand factor type D domain; this inhibition occurs even downstream of Smad1 activation and is not altered by neogenin overexpression.\",\n      \"method\": \"C2C12 myoblast reporter assays, domain deletion/mutant constructs, constitutively active receptor constructs, neogenin overexpression\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutagenesis, multiple BMP signaling readouts, single lab\",\n      \"pmids\": [\"19422419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RGMB (DRAGON) controls the balance of olfactory receptor neurons and sustentacular (glial-like) cells in the developing olfactory epithelium through interaction with neogenin; RGMB is expressed in newly born ORNs adjacent to neogenin-expressing progenitors; Rgmb ablation increases dividing progenitors and supernumerary SUS cells, phenocopied by neogenin loss-of-function.\",\n      \"method\": \"Gene-targeted Rgmb and Neo1 knockout mice, cell counting, BrdU incorporation, in situ hybridization, immunofluorescence\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genetic knockouts with specific quantitative cellular phenotypes, epistasis between RGMB and neogenin established\",\n      \"pmids\": [\"27143755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PD-L2 (B7-DC) K113S mutant (which cannot bind PD-1) retains RGMb binding with similar affinity to wild-type PD-L2, costimulates CD4+ T cells via RGMb and promotes Th1 polarization; RGMb is expressed on naive mouse T cells, macrophages, neutrophils, and dendritic cells; K113S/RGMb costimulation suppresses Th2-mediated asthma in vivo.\",\n      \"method\": \"Binding affinity assays, T cell co-stimulation assays, Th1/Th2 polarization assays, murine allergic asthma model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — binding and functional assays with PD-L2 mutant, in vivo disease model, single lab\",\n      \"pmids\": [\"28479601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RGMb protects against acute kidney injury (ischemia/reperfusion and oxalate nephropathy) by reducing membrane-associated MLKL levels and inhibiting necroptosis in proximal tubular cells; tubule-specific Rgmb conditional knockout increases MLKL at the apical membrane of proximal tubular cells and worsens renal dysfunction; necroptosis inhibitors (Necrostatin-1, GSK'963) ameliorate injury in both wild-type and Rgmb cKO mice.\",\n      \"method\": \"Conditional tubular Rgmb knockout mice, ischemia/reperfusion and oxalate nephropathy models, MLKL membrane fractionation, necroptosis inhibitor treatment, renal function assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout with specific molecular (MLKL) and functional (renal dysfunction) readouts, pharmacological rescue, in vivo\",\n      \"pmids\": [\"29382757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RGMB is a novel binding partner of CTLA-4; RGMB specifically strengthens binding of the monomeric soluble form of CTLA-4 (sCTLA-4) to CD80, thereby enhancing CTLA-4's suppressive effect on co-stimulation; RGMB is expressed at high levels in tolerogenic dendritic cell subsets.\",\n      \"method\": \"Pulldown/binding assays, co-stimulation suppression assays, CD80 binding enhancement assay, expression profiling of DC subsets\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding and functional co-stimulation assays, single lab, mechanistic follow-up limited\",\n      \"pmids\": [\"31061392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Blockade of RGMb with anti-RGMb mAb effectively blocks development of airway inflammation and airway hyperreactivity in ovalbumin and cockroach allergen murine asthma models; RGMb is expressed on bronchial epithelial cells, activated eosinophils, and interstitial macrophages; neogenin (canonical RGMb receptor) is expressed by interstitial macrophages and bronchial epithelial cells in inflamed lung; IL-25 pathway is required for the disease.\",\n      \"method\": \"Anti-RGMb mAb treatment in murine asthma models, IL-25 receptor-deficient mice, immunostaining for RGMb and neogenin\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — antibody blockade with defined phenotypic readout, genetic KO of IL-25R for epistasis, single lab\",\n      \"pmids\": [\"30703386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RGMB knockdown in breast cancer cells enhances proliferation, adhesion, and migration; mechanistically, knockdown reduces Caspase-3 expression/activity (improving survival under serum starvation) via repression of the MAPK JNK pathway, and increases Snai1, Twist, FAK, and Paxillin expression via enhanced Smad-dependent signaling.\",\n      \"method\": \"Ribozyme transgene knockdown of RGMB in breast cancer cells, proliferation/adhesion/migration assays, caspase activity assays, Western blotting for signaling molecules\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with multiple pathway readouts, single lab\",\n      \"pmids\": [\"22415859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dragon (RGMB) promotes colorectal cancer cell proliferation and tumor growth via BMP4-Smad1/5/8 and Erk1/2 pathways; Dragon expression is elevated in colon cancer tissues in mouse CAC model and human patients.\",\n      \"method\": \"RGMB overexpression in CT26.WT and CMT93 cells, xenograft mouse model, BMP4-Smad1/5/8 and Erk1/2 pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function with in vitro and in vivo tumor readouts, pathway analysis, single lab\",\n      \"pmids\": [\"26029998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dragon (RGMB) induces resistance to oxaliplatin in colon cancer cells by inhibiting oxaliplatin-induced JNK and p38 MAPK activation and blocking caspase-3 and PARP cleavage; Dragon-expressing xenograft tumors show reduced response to oxaliplatin.\",\n      \"method\": \"Dragon overexpression in CMT93/HCT116 cells, oxaliplatin treatment, apoptosis assays, JNK/p38 MAPK pathway analysis, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function with pharmacological challenge, pathway readouts, in vivo xenograft, single lab\",\n      \"pmids\": [\"27384995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF4 ubiquitin ligase promotes osteogenic differentiation of hBMSCs by transcriptionally upregulating both RGMb and BMP6; knockdown of either RGMb or BMP6 halts osteogenic differentiation; combined addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restores osteogenic differentiation, placing RGMb downstream of RNF4 in an RNF4–RGMb–BMP6 axis required for osteogenesis and osteosarcoma cell survival.\",\n      \"method\": \"RNF4/RGMb/BMP6 knockdown in hBMSCs, conditioned media rescue, purified protein add-back, osteosarcoma cell survival assays, transcriptional analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (knockdown of each component), purified protein reconstitution rescue, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"36153321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human sensory neurons secrete RGMB protein, which induces morphogenesis and melanin production in human melanocytes; RGMB was identified in sensory neuron-conditioned medium by proteomic analysis; transcriptome analysis indicates RGMB controls the melanosome transport machinery.\",\n      \"method\": \"Proteomic analysis of conditioned medium, co-culture of iPSC-derived sensory neurons with melanocytes, RGMB protein treatment of melanocytes, transcriptome analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification, direct protein treatment with functional readout, transcriptomic follow-up, single lab\",\n      \"pmids\": [\"36130522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The gut microbiome downregulates PD-L2 and its binding partner RGMb to promote anti-tumor immunity; antibody-mediated blockade of the PD-L2–RGMb pathway, or conditional deletion of RGMb in T cells, combined with anti-PD-1 or anti-PD-L1 overcomes microbiome-dependent resistance to checkpoint inhibitors in multiple mouse tumor models including germ-free, antibiotic-treated, and non-responder stool-colonized mice.\",\n      \"method\": \"Conditional T cell-specific RGMb knockout mice, anti-PD-L2/anti-RGMb antibody blockade, multiple syngeneic tumor models, germ-free and antibiotic-treated mouse experiments, fecal transplant experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout plus antibody blockade, multiple independent tumor models, microbiome manipulation, replicated across experimental conditions\",\n      \"pmids\": [\"37138075\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RGMB (DRAGON) is a GPI-anchored membrane protein that functions as a BMP co-receptor by directly binding BMP2/4 and associating with type I and type II BMP receptors to potentiate Smad1/5/8 and MAPK signaling; it also acts as a ligand for the neogenin receptor to control cell migration, neuronal/glial differentiation, and epithelial apoptosis independently of BMP; in the immune system it serves as a binding partner for both PD-L2 (regulating respiratory tolerance and anti-tumor immunity) and CTLA-4 (modulating co-stimulation), and in the kidney it suppresses MLKL-dependent necroptosis to protect against acute injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RGMB (DRAGON) is a GPI-anchored cell-surface protein that operates at the intersection of BMP signaling, neogenin-dependent guidance, and immune co-regulation [#0, #8, #20]. As a BMP co-receptor it directly binds BMP2 and BMP4 — but not BMP7 or other TGFβ ligands — associates with type I (ALK2/3/6) and type II (ActRII/ActRIIB) BMP receptors, and potentiates ligand-dependent Smad1/5/8 signaling in a manner blocked by Noggin and dominant-negative Smad1/ALK3/6 [#0]; it localizes to lipid rafts and apical epithelial surfaces and can redirect signaling through ActRIIA to modulate epithelial barrier function [#2, #3]. Beyond Smads, RGMB engages the p38/Erk MAPK arm to negatively regulate macrophage IL-6 [#4], and in some contexts suppresses BMP output via its von Willebrand factor type D domain independently of neogenin [#9]. Independently of BMP, RGMB acts as a ligand for the neogenin receptor to control precursor cell aggregation, migration, and neuron-versus-glia fate decisions in the developing nervous system [#8, #10], and through neogenin it drives E-cadherin loss and caspase-dependent apoptosis in renal tubular epithelium [#6]. In the immune system RGMB is a binding partner for PD-L2 — at a site distinct from the BMP-binding site — controlling respiratory tolerance, T cell co-stimulation, and microbiome-dependent anti-tumor immunity, such that blockade or T-cell-specific deletion of RGMB overcomes resistance to PD-1/PD-L1 checkpoint inhibition [#7, #11, #20]; it also binds CTLA-4 to strengthen sCTLA-4 engagement of CD80 [#13]. In the kidney, RGMB protects against acute injury by limiting membrane-associated MLKL and inhibiting necroptosis in proximal tubular cells [#12]. RGMB further functions as a secreted regulator of melanocyte morphogenesis and an RNF4-induced effector required for osteogenic differentiation via an RNF4–RGMB–BMP6 axis [#18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing RGMB's first molecular identity, it was defined as a GPI-anchored, DRG11-regulated adhesion molecule, setting it as a sensory-system membrane protein before any signaling role was known.\",\n      \"evidence\": \"Promoter/genomic binding analysis, DRG11-null expression analysis, and homophilic adhesion assays in DRG neurons\",\n      \"pmids\": [\"14985445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor partner identified at this stage\", \"Adhesion mechanism and binding partners undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The central biochemical function was resolved by showing RGMB is a BMP co-receptor that selectively binds BMP2/4 and associates with type I/II BMP receptors to amplify Smad1/5/8 signaling.\",\n      \"evidence\": \"Direct binding/co-IP with BMP receptors, dominant-negative Smad1/ALK3/6, Noggin inhibition, and Xenopus overexpression\",\n      \"pmids\": [\"15671031\", \"15890774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ligand selectivity not resolved\", \"How GPI-anchoring couples to receptor complex assembly unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"RGMB was shown to act as a neogenin ligand controlling precursor migration, establishing a BMP-independent signaling axis, while a separate study showed it can also suppress BMP output through its vWF type D domain.\",\n      \"evidence\": \"Reciprocal co-IP/binding with neogenin plus organotypic slice and in utero migration assays; domain-deletion reporter assays in C2C12 myoblasts\",\n      \"pmids\": [\"19944164\", \"19422419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context determining co-receptor potentiation versus suppression unresolved\", \"Downstream neogenin effectors in migration not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tissue-specific signaling outputs were defined, showing RGMB enhances Smad-dependent barrier function in kidney epithelium via ActRIIA and negatively regulates macrophage IL-6 through MAPK rather than Smad.\",\n      \"evidence\": \"Kidney immunolocalization and mIMCD3 receptor-knockdown/transepithelial resistance assays; macrophage cell lines, Dragon-knockout mice, and MAPK inhibitor dissection\",\n      \"pmids\": [\"20167703\", \"21187450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of receptor switching to ActRIIA unknown\", \"How RGMB selects Smad versus MAPK output not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic loss-of-function established a physiological developmental requirement, with RGMb promoting BMP-2-dependent neurite outgrowth and peripheral nerve regeneration.\",\n      \"evidence\": \"RGMb knockout DRG neuron cultures with BMP-2 rescue and in vivo sciatic nerve crush\",\n      \"pmids\": [\"22171041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor complex mediating regenerative effect not specified\", \"Relative contribution of BMP versus neogenin in regeneration unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A pro-apoptotic, neogenin-dependent role was demonstrated, expanding RGMB beyond a growth-promoting co-receptor to a driver of epithelial cell death and E-cadherin loss in injured kidney.\",\n      \"evidence\": \"IMCD3 overexpression with neogenin knockdown, caspase/PARP assays, and ureteral obstruction in heterozygous knockout mice\",\n      \"pmids\": [\"24052264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling linking neogenin to caspase activation not delineated\", \"Reconciliation with protective renal roles unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"RGMB was identified as a PD-L2 binding partner with a distinct binding site from BMP, defining a new immune-checkpoint-adjacent function in respiratory tolerance.\",\n      \"evidence\": \"Binding assays with site-mapping, PD-L2-deficient mice, and anti-RGMb/anti-PD-L2 blockade in respiratory tolerance models\",\n      \"pmids\": [\"24752301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling triggered by RGMb–PD-L2 engagement undefined\", \"Cell-type-specific outputs of the interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The PD-L2–RGMb axis was shown to be PD-1-independent and co-stimulatory, with PD-L2 driving Th1 polarization and suppressing Th2 asthma via RGMb.\",\n      \"evidence\": \"PD-L2 K113S mutant binding/co-stimulation assays, Th1/Th2 polarization, and murine allergic asthma model\",\n      \"pmids\": [\"28479601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RGMb-proximal signaling in T cell co-stimulation not mapped\", \"Single lab, requires independent confirmation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A cytoprotective mechanism distinct from its pro-apoptotic role was defined, with RGMb limiting membrane MLKL to inhibit necroptosis and protect tubular cells in acute kidney injury.\",\n      \"evidence\": \"Tubule-specific conditional Rgmb knockout in ischemia/reperfusion and oxalate nephropathy, MLKL membrane fractionation, and necroptosis-inhibitor rescue\",\n      \"pmids\": [\"29382757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between RGMb and MLKL regulation unknown\", \"Whether this is BMP- or neogenin-dependent not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"RGMB's immune-modulatory repertoire was broadened by identifying it as a CTLA-4 binding partner that strengthens sCTLA-4–CD80 engagement, and by showing anti-RGMb blockade suppresses allergic airway disease.\",\n      \"evidence\": \"Pulldown/binding and co-stimulation suppression assays with CD80; anti-RGMb mAb in ovalbumin/cockroach asthma models with IL-25R-deficient mice\",\n      \"pmids\": [\"31061392\", \"30703386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CTLA-4 interaction not resolved\", \"Receptor mediating RGMb effects in airway inflammation not pinned down\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two new effector functions were established: RGMB as a secreted regulator of melanocyte morphogenesis/melanin and as an RNF4-induced node in an RNF4–RGMB–BMP6 osteogenic axis.\",\n      \"evidence\": \"Proteomic identification from sensory neuron-conditioned medium with melanocyte treatment; RNF4/RGMb/BMP6 knockdown and purified-protein add-back rescue in hBMSCs\",\n      \"pmids\": [\"36130522\", \"36153321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Melanocyte receptor for secreted RGMB unidentified\", \"How RNF4 transcriptionally controls RGMB not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The therapeutic significance of the RGMb–PD-L2 axis was established, showing the gut microbiome regulates this pathway and that blocking or deleting RGMb in T cells overcomes microbiome-dependent checkpoint-inhibitor resistance.\",\n      \"evidence\": \"T-cell-specific conditional Rgmb knockout, anti-RGMb/anti-PD-L2 blockade across syngeneic tumor models, and germ-free/antibiotic/fecal-transplant experiments\",\n      \"pmids\": [\"37138075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling downstream of RGMb in T cells unresolved\", \"Microbiome-to-RGMb regulatory mechanism not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single GPI-anchored protein integrates BMP co-receptor signaling, neogenin ligand activity, and PD-L2/CTLA-4 immune binding into context-specific outputs — and the structural and intracellular basis of each — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of RGMB's multiple binding interfaces\", \"Determinants selecting Smad versus MAPK versus neogenin output unknown\", \"Proximal intracellular signaling of GPI-anchored RGMB undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [8, 10, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9, 13]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 13, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 10, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BMP2\", \"BMP4\", \"ALK3\", \"ActRIIA\", \"NEO1\", \"PDCD1LG2\", \"CTLA4\", \"BMP6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}