{"gene":"MAGED1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"NRAGE (MAGED1) directly binds the p75 neurotrophin receptor (p75NTR) intracellular domain in vitro and in vivo; this interaction is functionally exclusive with TrkA binding to p75NTR. NRAGE association with the plasma membrane occurs when NGF is bound to p75NTR, and NRAGE overexpression facilitates cell cycle arrest and NGF-dependent apoptosis in sympathetic neuron precursors.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, overexpression in sympathetic neuron precursor cells","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and in vitro binding with functional consequence (apoptosis), replicated by multiple subsequent studies","pmids":["10985348"],"is_preprint":false},{"year":2002,"finding":"NRAGE-induced apoptosis proceeds through a JNK-dependent mitochondrial pathway: induced NRAGE expression activates JNK, causes cytosolic accumulation of cytochrome c, and activates caspases-3, -7, and -9; blocking JNK or dominant-negative c-Jun ablates NRAGE-mediated caspase activation and cell death.","method":"Inducible recombinant NRAGE adenovirus, pharmacological JNK inhibition, dominant-negative overexpression, cytochrome c fractionation, caspase activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (pharmacological inhibition, dominant-negative, biochemical fractionation) in single rigorous study establishing the mechanistic pathway","pmids":["12376548"],"is_preprint":false},{"year":2000,"finding":"MAGED1 (Dlxin-1) binds Dlx5, Dlx7, and Msx2 homeodomain proteins through its hexapeptide repeat domain, forms homomultimers in vivo, and activates Dlx5-dependent transcriptional function in reporter gene assays.","method":"Yeast two-hybrid, co-immunoprecipitation, transfection/reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assay, replicated by multiple subsequent studies","pmids":["11084035"],"is_preprint":false},{"year":2002,"finding":"The RING finger E3 ubiquitin ligase Praja1 binds the C-terminal necdin homology domain of MAGED1 (Dlxin-1) and promotes its ubiquitination and proteasome-dependent degradation, thereby down-regulating Dlx5-dependent transcriptional activity.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, proteasome inhibitor rescue, RING-finger mutant, in vivo ubiquitination assay, reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding, in vivo ubiquitination assay with mutagenesis, proteasome inhibitor rescue, and functional reporter assay in one study","pmids":["11959851"],"is_preprint":false},{"year":2003,"finding":"UNC5H1 induces apoptosis through a direct interaction between its ZU-5 domain (plus adjacent PEST sequence) and NRAGE; chimeric UNC5H2/3 receptors engineered with this region gain NRAGE binding and increased apoptosis, and UNC5H1 fails to induce apoptosis in PC12 cells lacking endogenous NRAGE.","method":"Co-immunoprecipitation, domain mapping with chimeric receptors, NRAGE knockdown/overexpression in PC12 cells, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping, chimeric receptor rescue, and loss/gain of function, multiple orthogonal approaches in single study","pmids":["12598531"],"is_preprint":false},{"year":2003,"finding":"Ror2 (but not Ror1) associates with MAGED1 (Dlxin-1) via its cytoplasmic C-terminal proline/serine-threonine-rich region interacting with the necdin homology domain of Dlxin-1. This interaction sequesters Dlxin-1 in membranous compartments, preventing its nuclear localization, and thereby modulates Msx2 transcriptional activity.","method":"Co-immunoprecipitation, transient expression, immunohistochemistry, subcellular fractionation of Ror2−/− fibroblasts, reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, knockout fibroblast fractionation, and functional reporter assay in one study","pmids":["12754255"],"is_preprint":false},{"year":2004,"finding":"MAGED1 directly interacts with necdin via its MAGE homology domain and with Msx1/Msx2 via its hexapeptide repeat domain, forming a ternary complex that releases Msx-dependent transcriptional repression and promotes myogenic differentiation of C2C12 cells.","method":"In vitro binding assay, co-immunoprecipitation, endogenous complex detection in differentiating cells, transcriptional reporter assay, stable transfection + differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ternary complex reconstituted in vitro and detected endogenously, with functional differentiation assay","pmids":["15272023"],"is_preprint":false},{"year":2005,"finding":"NRAGE is a mandatory component of the non-canonical BMP signaling cascade: NRAGE binds and functions with the TAK1-TAB1-XIAP complex to activate p38 MAPK and induce apoptosis in neural progenitors; disruption of NRAGE blocks p38 activation independently of Smad signaling.","method":"Co-immunoprecipitation, dominant-negative constructs, siRNA knockdown, p38 phosphorylation assays, apoptosis assays in neural progenitors","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function approaches with defined biochemical readouts, replicated by subsequent studies","pmids":["16107717"],"is_preprint":false},{"year":2005,"finding":"BRCA2 binds and stabilizes MAGED1 protein; expression of BRCA2 and MAGED1 synergistically suppresses cell proliferation independently of the p53 pathway, and MAGED1 expression is required for BRCA2-mediated growth suppression.","method":"Co-immunoprecipitation, RNAi knockdown of MAGED1, cell proliferation assays in multiple cell lines","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RNAi epistasis, single lab with two orthogonal methods","pmids":["15930293"],"is_preprint":false},{"year":2005,"finding":"Cytosolic PrP(C) constructs interact directly with NRAGE (identified by yeast two-hybrid, confirmed by in vitro binding and co-immunoprecipitation); co-expression of NRAGE and cytosolic PrP affects mitochondrial membrane potential, and NRAGE accumulates in perinuclear aggresomes upon proteasome inhibition.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, subcellular localization (co-localization in aggresomes), mitochondrial membrane potential assay","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding confirmations plus functional mitochondrial readout, single lab","pmids":["15911347"],"is_preprint":false},{"year":2007,"finding":"NRAGE interacts with the anti-apoptotic factor Che-1/AATF and sequesters it in the cytoplasm, preventing nuclear localization; NRAGE overexpression promotes proteasome-dependent degradation of Che-1, and Che-1 overexpression completely reverts NRAGE-induced cell death.","method":"Co-immunoprecipitation, EGFP-NRAGE subcellular localization, proteasome inhibitor assay, overexpression rescue experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, localization, proteasome rescue, and functional rescue, single lab with multiple methods","pmids":["17488777"],"is_preprint":false},{"year":2008,"finding":"NRAGE is required in vivo for developmental apoptosis: NRAGE knockout mice have defects in sympathetic neuron apoptosis similar to p75NTR knockouts, show attenuated BDNF-dependent JNK activation, exhibit identical hair follicle catagen defects as p75NTR knockouts, and display additional motoneuron apoptosis defects not seen in p75NTR knockouts.","method":"NRAGE knockout mouse generation, histological apoptosis quantification, primary sympathetic neuron culture, JNK activation assay, hair follicle analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple in vivo and in vitro mechanistic readouts, co-expression and phenocopy evidence with p75NTR KO","pmids":["18772898"],"is_preprint":false},{"year":2010,"finding":"MAGED1 binds RORα and regulates circadian clock gene expression (Bmal1, Rev-erbα, E4bp4) through RORE elements; Maged1 knockout mice show shortened circadian period and altered rest-activity bouts, demonstrating MAGED1 is required for robustness of the molecular clock.","method":"Genetic screen, Maged1 knockout mice behavioral analysis, in vitro and in vivo binding assays, reporter gene assays with RORE elements","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout phenotype plus direct binding and reporter assay evidence in vivo and in vitro, multiple orthogonal methods","pmids":["20300063"],"is_preprint":false},{"year":2010,"finding":"NRAGE is a negative regulator of NGF-induced neurite outgrowth: NRAGE knockdown accelerates NGF-mediated neurite outgrowth and increases TrkA-ERK activation; NRAGE downregulates TrkA expression post-transcriptionally and blocks NGF-induced TrkA phosphorylation at tyrosine-490.","method":"RNAi knockdown, overexpression, MEK inhibitor treatment, TrkA phosphorylation assays, neurite outgrowth quantification in PC12 cells","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss/gain of function with defined biochemical (TrkA phosphorylation) and cellular (neurite outgrowth) readouts, single lab","pmids":["20127820"],"is_preprint":false},{"year":2010,"finding":"NRAGE acts via the XIAP-TAK1-TAB1 complex to activate IKK-α/β phosphorylation and NF-κB transcriptional activation in the non-canonical BMP pathway; siRNA ablation of NRAGE inhibits NF-κB activation, and ablation of TAK1/TAB1 blocks NRAGE-induced NF-κB activation.","method":"siRNA knockdown, morpholino knockdown, IKK phosphorylation assay, NF-κB luciferase reporter assay, cytokine profiling","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double knockdown, reporter assay, single lab multiple methods","pmids":["20100315"],"is_preprint":false},{"year":2011,"finding":"NRAGE's unique hexapeptide repeat domain directly interacts with XIAP (demonstrated by FRET), and this domain is responsible for downstream NF-κB activation and IKK subunit phosphorylation in BMP signaling; a peptide modeled after this repeat domain inhibits NF-κB activation and apoptosis in P19 cells.","method":"FRET, deletion mutagenesis, p38 phosphorylation assay, caspase-3 cleavage assay, NF-κB reporter assay, peptide inhibitor","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET for direct interaction, domain mapping by deletion, functional assays, single lab","pmids":["21789165"],"is_preprint":false},{"year":2012,"finding":"MAGED1 binds SERT (serotonin transporter) via its necdin homology domain and promotes SERT ubiquitylation; MAGED1 knockout mice show hypoactive serotonergic function with hyperexpression of SERT due to decreased ubiquitylation, and MAGED1 overexpression decreases SERT protein level and serotonin uptake activity.","method":"Co-immunoprecipitation, MAGED1 knockout mice, siRNA knockdown, ubiquitylation assays, serotonin uptake assays, Western blot","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse, in vitro ubiquitylation, domain-mapped binding, and functional serotonin uptake assay, multiple orthogonal methods","pmids":["22457503"],"is_preprint":false},{"year":2012,"finding":"Loss of Maged1 severely reduces mature oxytocin levels in the hypothalamus without reducing precursor levels, indicating MAGED1 is required for OT processing or stability; oxytocin administration rescues social memory deficits in Maged1 knockout mice.","method":"Maged1 knockout mice, RIA/ELISA for oxytocin and precursors, OT rescue experiment, behavioral assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with peptide-level biochemistry and pharmacological rescue, single lab","pmids":["22865874"],"is_preprint":false},{"year":2012,"finding":"NRAGE blocks the Ror2-Src interaction and inhibits Ror2-mediated cell migration by decreasing Src and focal adhesion kinase (FAK) activity; NRAGE sharply blocks the interaction between Src SH1 domain and the C-terminus of Ror2.","method":"Co-immunoprecipitation, kinase activity assays, overexpression/knockdown, migration assay in B16/B16-BL6 cells","journal":"Cancer genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex, kinase activity assay, and functional migration assay, single lab","pmids":["23142633"],"is_preprint":false},{"year":2013,"finding":"The ubiquitin ligase Praja1 co-localizes with NRAGE and reduces NRAGE levels via proteasome-dependent degradation; Praja1 overexpression suppresses NGF-induced neurite formation in PC12 cells through NRAGE degradation.","method":"Co-localization (immunofluorescence), Western blot, proteasome inhibitor rescue, stable overexpression in PC12 cells, neurite assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteasome inhibitor rescue plus functional neurite assay, single lab","pmids":["23717400"],"is_preprint":false},{"year":2014,"finding":"MAGED1 co-interacts with CREB through its hexapeptide repeat domain; Maged1 knockout reduces CREB-dependent transcription and BDNF levels, and is associated with impaired long-term potentiation and spatial learning.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, LTP electrophysiology, Maged1 knockout mice, Western blot","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and reporter assay plus KO phenotype, single lab","pmids":["24700102"],"is_preprint":false},{"year":2014,"finding":"NRAGE physically interacts with PCNA via DNA polymerase III subunit and stabilizes PCNA by reducing K48-linked polyubiquitination; knockdown of NRAGE promotes PCNA proteasomal degradation via USP10 regulation, and PCNA overexpression rescues growth inhibition in NRAGE-deficient esophageal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, USP10 identification, cell growth/cycle assays, rescue by PCNA overexpression, in vivo xenograft","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and rescue experiment, single lab","pmids":["24710624"],"is_preprint":false},{"year":2014,"finding":"FBXO7 interacts with NRAGE and mediates Lys-63-linked (non-degradative) polyubiquitination of NRAGE; this promotes formation of the NRAGE-TAK1-TAB1 and BMP receptor-NRAGE-TAK1-TAB1 complexes and upregulates NF-κB activity.","method":"Yeast two-hybrid, co-immunoprecipitation, K63-linked ubiquitination assay, FBXO7 knockdown/overexpression, NF-κB reporter assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, and reporter assay, single lab","pmids":["24947323"],"is_preprint":false},{"year":2015,"finding":"p75NTR-dependent Rac1 activation requires proteolytic cleavage of p75NTR (by ADAM17 and γ-secretase) to generate the intracellular domain (ICD), and the ICD signals through NRAGE and a newly identified NRAGE-binding partner NEDD9 to activate Rac1 and promote cell spreading.","method":"Bioassay in COS7 cells, pharmacological cleavage inhibitors, yeast two-hybrid for NEDD9, co-immunoprecipitation, Rac1 activation assay, dominant-negative constructs","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel interaction by yeast two-hybrid confirmed by Co-IP, epistasis by pharmacological and dominant-negative approaches, single lab","pmids":["25472715"],"is_preprint":false},{"year":2016,"finding":"NRAGE is required for efficient homologous recombination repair of double-strand breaks; NRAGE regulates stability of RNF8 and BARD1 via ubiquitin-proteolytic pathway and forms a ternary complex with RNF8 and BARD1 (via their RING domains), facilitating their interaction and DDR.","method":"Co-immunoprecipitation (ternary complex), ubiquitination assay, HRR reporter assay, knockdown with DNA damage sensitivity assays in vitro and in vivo xenograft","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ternary complex Co-IP, ubiquitin assay, and functional HRR assay, single lab","pmids":["27035619"],"is_preprint":false},{"year":2016,"finding":"MAGED1 binds and positively regulates a select subset of bHLH PAS transcription factors (SIM1, SIM2, NPAS4, ARNT2) but not others (AhR, HIF1α, ARNT); interaction is mediated by PAS repeat regions and MAGED1 appears to interact with nascent bHLH PAS proteins in the cytoplasm to enhance their function prior to nuclear import, without affecting their protein levels.","method":"Co-immunoprecipitation, transcriptional reporter assay, subcellular localization analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective binding confirmed by Co-IP with reporter assay, subcellular localization, single lab","pmids":["27472814"],"is_preprint":false},{"year":2017,"finding":"Necdin promotes osteoblast differentiation through formation of a complex with MAGED1 and Dlx5, and activation of Runx2 promoter; co-expression of necdin and MAGED1 is required to achieve osteoblast-specific marker induction.","method":"Co-immunoprecipitation, stable transfection, osteoblast differentiation assay, Runx2 reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating ternary complex, reporter assay, differentiation assay, single lab","pmids":["28528976"],"is_preprint":false},{"year":2017,"finding":"NRAGE induces O-GlcNAcylation of β-catenin/Arm, which causes failure of the association between β-catenin and pygopus (required for Wnt target gene transcription), thereby suppressing Wnt pathway output despite promoting β-catenin nuclear localization.","method":"Reporter assay, RNAi, Xenopus axis duplication assay, O-GlcNAc modification detection, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Xenopus assay, post-translational modification detection, Co-IP, multiple methods but single lab","pmids":["28427939"],"is_preprint":false},{"year":2018,"finding":"MAGED1 binds PPARγ and suppresses its stability and transcriptional activity; MAGED1-deficient mice show increased PPARγ protein levels, more adipocyte precursors, and hyperplasia of white adipose tissue, with improved insulin sensitivity.","method":"Co-immunoprecipitation, MAGED1 knockout mice, PPARγ stability assay, target gene expression, adipocyte differentiation assay","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus knockout mouse with biochemical and cellular readouts, single lab","pmids":["30121577"],"is_preprint":false},{"year":2018,"finding":"Maged1 is critical for cortico-accumbal neurotransmission and cocaine-induced dopamine release in the nucleus accumbens; expression of Maged1 in the prefrontal cortex and amygdala (but not in dopaminergic or striatal GABAergic neurons) is required for cocaine-mediated behavioral sensitization.","method":"Maged1 knockout mice, conditional knockout (cell-type specific), electrophysiology in brain slices, in vivo microdialysis, conditioned place preference, drug self-administration","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-type specificity, electrophysiology, and in vivo dopamine measurement, multiple orthogonal methods","pmids":["30002119"],"is_preprint":false},{"year":2010,"finding":"Maged1 deficiency results in reduced p21CIP1/WAF1 levels, defective cell cycle exit, and impaired myotube maturation during myoblast differentiation; in vivo this causes delayed muscle regeneration after injury.","method":"Maged1 knockout mice, in vitro myoblast differentiation, p21 Western blot, cell cycle analysis, in vivo muscle injury model","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with defined molecular (p21) and cellular (differentiation, regeneration) readouts, single lab","pmids":["20646279"],"is_preprint":false},{"year":2018,"finding":"NRAGE binds IKKβ (co-immunoprecipitation) and inhibits the NF-κB signaling pathway; NRAGE knockdown promotes odontogenic differentiation through increased NF-κB1 nuclear translocation and p65 phosphorylation, effects reversed by an IKK inhibitor.","method":"Co-immunoprecipitation, confocal microscopy, lentivirus-mediated shRNA knockdown, IKK inhibitor, differentiation assays","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying IKKβ as binding partner, pharmacological rescue, and functional differentiation assay, single lab","pmids":["29448842"],"is_preprint":false},{"year":2020,"finding":"The CDK4/6-E2F1 signaling axis increases MAGED1 expression, which in turn promotes FBP1 degradation and aerobic glycolysis (Warburg effect) in pancreatic cancer; CDK4/6 inhibitor PD0332991 stabilizes FBP1 by repressing MAGED1 expression.","method":"CDK4/6 inhibitor treatment, E2F1 reporter assay, FBP1 stability assay, glycolysis measurements","journal":"The international journal of biochemistry & cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological and expression data, mechanism inferred without direct protein-protein interaction confirmation, single lab","pmids":["32987196"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 recognizes m6A-modified MAGED1 mRNA and promotes its translation in an m6A-dependent manner (absent in METTL3-deficient cells); increased MAGED1 protein promotes PASMC proliferation through PCNA upregulation and contributes to pulmonary hypertension.","method":"m6A-RIP sequencing, RNA immunoprecipitation, YTHDF1 knockout mice, MAGED1 genetic ablation, METTL3 knockout, PCNA Western blot, proliferation assays","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP, METTL3-KO mechanistic control, and genetic ablation with defined molecular readout (PCNA), single lab","pmids":["33465322"],"is_preprint":false},{"year":2023,"finding":"Maged1 acts as a scaffold that partners with USP7 to regulate H2A monoubiquitination in paraventricular thalamus (PVT) neurons; chronic cocaine use increases H2A monoubiquitination in PVT, and Maged1-specific inactivation in thalamic Vglut2 neurons or USP7 inhibition blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization.","method":"Conditional Maged1 knockout (Vglut2-Cre), USP7 pharmacological inhibition, H2A monoubiquitination ChIP, locomotor sensitization behavioral assay, transcriptome analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cell-type-specific KO, ChIP for epigenetic mark, pharmacological inhibition, and behavioral assay, multiple orthogonal methods","pmids":["38123574"],"is_preprint":false},{"year":2026,"finding":"A frameshift variant in MAGED1 (Leu137PhefsTer4) disrupts the interaction between MAGED1 and the E3 ubiquitin ligase Praja-1 (co-immunoprecipitation), impairs degradation of the truncated protein leading to its abnormal stabilization, and abolishes MAGED1's inhibitory effect on cell migration.","method":"Co-immunoprecipitation, immunofluorescence, Western blot, wound healing assay, cell cycle/apoptosis assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction disruption, protein stability assay, and functional migration assay, single lab with variant-specific mechanistic follow-up","pmids":["42162770"],"is_preprint":false}],"current_model":"MAGED1 (NRAGE/Dlxin-1) is a multifunctional scaffold/adaptor protein that operates at the intersection of several signaling pathways: it directly binds p75NTR and blocks its association with TrkA to facilitate NGF-dependent apoptosis via a JNK-mitochondrial-caspase cascade; it engages the TAK1-TAB1-XIAP complex downstream of BMP receptors to activate p38 MAPK and NF-κB; it binds Dlx/Msx homeodomain transcription factors through its hexapeptide repeat domain to modulate transcription; it serves as an adaptor for E3 ubiquitin ligases (Praja1, FBXO7) that control its own stability and the stability of substrates including SERT, PCNA, Che-1/AATF, and PPARγ; it interacts with RORα to regulate circadian clock gene expression; in neurons it partners with NEDD9 downstream of the p75NTR intracellular domain to activate Rac1; and in the paraventricular thalamus it partners with USP7 to regulate H2A monoubiquitination and cocaine-adaptive behaviors."},"narrative":{"mechanistic_narrative":"MAGED1 (NRAGE/Dlxin-1) is a multifunctional scaffold/adaptor protein that integrates neurotrophin, BMP, transcription-factor and ubiquitin signaling to control developmental apoptosis, differentiation and neural function [PMID:10985348, PMID:16107717, PMID:18772898]. In the neurotrophin axis it binds the p75NTR intracellular domain in a manner mutually exclusive with TrkA and drives NGF-dependent apoptosis through a JNK–mitochondrial–caspase cascade, a function genetically required in vivo where NRAGE-null mice phenocopy p75NTR knockouts in sympathetic neuron and hair-follicle apoptosis [PMID:10985348, PMID:12376548, PMID:18772898]. The same membrane-proximal signaling also generates a p75NTR ICD that, with the NRAGE partner NEDD9, activates Rac1, while NRAGE conversely restrains TrkA-ERK signaling and neurite outgrowth [PMID:25472715, PMID:20127820]. In non-canonical BMP signaling NRAGE is an obligatory component that engages the TAK1–TAB1–XIAP complex via its hexapeptide repeat domain to activate p38 MAPK and IKK/NF-κB [PMID:16107717, PMID:20100315, PMID:21789165]. Through that hexapeptide repeat and a necdin-homology domain it binds Dlx/Msx homeodomain factors and necdin to form ternary complexes that relieve Msx repression and promote myogenic and osteogenic differentiation [PMID:11084035, PMID:15272023, PMID:28528976]. NRAGE further acts as an adaptor coupling substrates to the ubiquitin system: it is itself degraded by the RING E3 ligase Praja1 and receives K63 ubiquitination from FBXO7, and it controls the stability or modification of SERT, PCNA, Che-1/AATF, PPARγ, RNF8/BARD1 and H2A [PMID:11959851, PMID:24947323, PMID:22457503, PMID:24710624, PMID:17488777, PMID:30121577, PMID:27035619, PMID:38123574]. It binds RORα to sustain robustness of the circadian clock and partners with USP7 in paraventricular thalamus neurons to regulate H2A monoubiquitination and cocaine-adaptive behavior [PMID:20300063, PMID:38123574, PMID:30002119]. A frameshift variant (Leu137PhefsTer4) that abolishes Praja1-dependent degradation and the protein's anti-migratory function links MAGED1 dysfunction to disease [PMID:42162770].","teleology":[{"year":2000,"claim":"Established MAGED1's founding role as a death-promoting adaptor by showing it binds the p75NTR intracellular domain in competition with TrkA, linking a receptor to an apoptotic outcome.","evidence":"Yeast two-hybrid, in vitro binding and Co-IP with overexpression in sympathetic neuron precursors","pmids":["10985348"],"confidence":"High","gaps":["Did not define the downstream death machinery","Did not resolve which domain mediates p75NTR binding"]},{"year":2000,"claim":"Defined a parallel transcriptional function by showing MAGED1 binds Dlx/Msx homeodomain factors through its hexapeptide repeat and modulates their activity.","evidence":"Yeast two-hybrid, Co-IP, reporter gene assays","pmids":["11084035"],"confidence":"High","gaps":["Did not connect transcriptional and apoptotic roles","In vivo developmental relevance untested"]},{"year":2002,"claim":"Resolved the apoptotic cascade downstream of NRAGE as a JNK-dependent mitochondrial-caspase pathway, converting the binding observation into a defined mechanism.","evidence":"Inducible NRAGE adenovirus, JNK inhibition, dominant-negative c-Jun, cytochrome c fractionation, caspase assays","pmids":["12376548"],"confidence":"High","gaps":["How NRAGE activates JNK was not identified","Did not test requirement in vivo"]},{"year":2002,"claim":"Identified the first regulator of NRAGE stability, showing Praja1 ubiquitinates and degrades it to down-regulate Dlx5-dependent transcription.","evidence":"GST pulldown, Co-IP, in vivo ubiquitination, RING mutant, proteasome rescue, reporter assay","pmids":["11959851"],"confidence":"High","gaps":["Physiological context of degradation not defined","Other E3 ligases not excluded"]},{"year":2003,"claim":"Broadened NRAGE's death-receptor partners beyond p75NTR and defined a Ror2-dependent sequestration mechanism controlling its subcellular distribution and transcriptional output.","evidence":"Co-IP, domain mapping with chimeric UNC5H receptors, knockdown in PC12 cells, knockout fibroblast fractionation, reporter assays","pmids":["12598531","12754255"],"confidence":"High","gaps":["Did not unify nuclear vs membrane localization control","Crosstalk between receptor partners untested"]},{"year":2004,"claim":"Showed MAGED1 nucleates a necdin–Msx ternary complex that relieves transcriptional repression and promotes myogenic differentiation, defining a domain-resolved adaptor logic.","evidence":"In vitro binding, endogenous complex detection, reporter and differentiation assays in C2C12 cells","pmids":["15272023"],"confidence":"High","gaps":["In vivo myogenic requirement not shown here","Did not address other homeodomain partners"]},{"year":2005,"claim":"Established NRAGE as a mandatory, Smad-independent component of non-canonical BMP signaling by linking it to the TAK1-TAB1-XIAP module driving p38 activation.","evidence":"Co-IP, dominant-negative and siRNA loss-of-function, p38 phosphorylation and apoptosis assays in neural progenitors","pmids":["16107717"],"confidence":"High","gaps":["Direct XIAP-binding domain not yet mapped","Receptor-level recruitment unresolved"]},{"year":2005,"claim":"Extended NRAGE's interactome to growth-suppression (BRCA2) and to a cytosolic prion-protein/mitochondrial axis, hinting at broader regulatory roles.","evidence":"Co-IP, RNAi epistasis, proliferation assays; yeast two-hybrid, in vitro binding and mitochondrial membrane potential assays","pmids":["15930293","15911347"],"confidence":"Medium","gaps":["Single-lab observations","Mechanism linking these partners to apoptosis unclear"]},{"year":2007,"claim":"Showed NRAGE drives death partly by cytoplasmic sequestration and proteasomal degradation of the anti-apoptotic factor Che-1/AATF.","evidence":"Co-IP, EGFP localization, proteasome inhibitor and overexpression rescue","pmids":["17488777"],"confidence":"Medium","gaps":["E3 ligase for Che-1 not identified","In vivo relevance untested"]},{"year":2008,"claim":"Provided genetic proof that NRAGE is required in vivo for developmental apoptosis, phenocopying and extending p75NTR knockout phenotypes.","evidence":"NRAGE knockout mice, apoptosis quantification, primary neuron culture, JNK assays, hair follicle analysis","pmids":["18772898"],"confidence":"High","gaps":["Motoneuron-specific p75NTR-independent mechanism unresolved","Did not address non-apoptotic roles"]},{"year":2010,"claim":"Diversified MAGED1's physiology into circadian, neurotrophic-outgrowth, NF-κB and myogenic regulation, showing it tunes diverse transcriptional and signaling outputs.","evidence":"Maged1 knockout behavioral analysis with RORα binding/reporter assays; RNAi/overexpression of TrkA signaling; XIAP-TAK1-TAB1/IKK NF-κB assays; knockout myoblast differentiation with p21 readout","pmids":["20300063","20127820","20100315","20646279"],"confidence":"High","gaps":["Tissue-specific contributions of each role not separated","Direct vs indirect transcriptional effects mixed"]},{"year":2011,"claim":"Mapped the unique hexapeptide repeat domain as the direct XIAP-binding and NF-κB-activating module, enabling a peptide inhibitor of the pathway.","evidence":"FRET, deletion mutagenesis, p38/caspase/NF-κB assays, peptide inhibitor in P19 cells","pmids":["21789165"],"confidence":"Medium","gaps":["Structural basis of the interaction unresolved","Single-lab functional readouts"]},{"year":2012,"claim":"Defined MAGED1 as a substrate-targeting adaptor for ubiquitylation of SERT and as required for oxytocin maturation, linking it to monoaminergic and neuropeptide systems and behavior.","evidence":"Knockout mice with ubiquitylation/serotonin uptake assays; oxytocin RIA/ELISA and OT rescue with behavior","pmids":["22457503","22865874"],"confidence":"Medium","gaps":["E3 ligase partnering MAGED1 on SERT not defined","Mechanism of oxytocin processing role unknown"]},{"year":2012,"claim":"Showed NRAGE restrains Ror2-Src-FAK signaling to inhibit cell migration, adding a cytoskeletal/motility arm to its functions.","evidence":"Co-IP of ternary complex, kinase activity and migration assays in B16 cells","pmids":["23142633"],"confidence":"Medium","gaps":["In vivo metastasis relevance untested","Direct vs scaffold-mediated Src inhibition unclear"]},{"year":2013,"claim":"Connected Praja1-mediated NRAGE degradation to a cellular output, showing it controls NGF-induced neurite formation.","evidence":"Co-localization, proteasome rescue, stable overexpression and neurite assays in PC12 cells","pmids":["23717400"],"confidence":"Medium","gaps":["Signal regulating Praja1 activity unknown","In vivo relevance untested"]},{"year":2014,"claim":"Expanded MAGED1's ubiquitin-adaptor and transcriptional repertoire, linking it to PCNA stabilization, CREB-dependent transcription/synaptic plasticity, and FBXO7-mediated K63 ubiquitination that builds the BMP signaling complex.","evidence":"Co-IP/ubiquitination/USP10 and rescue assays for PCNA; Co-IP/ChIP/reporter with KO LTP for CREB; yeast two-hybrid, K63-linked ubiquitination and NF-κB reporter for FBXO7","pmids":["24710624","24700102","24947323"],"confidence":"Medium","gaps":["How a single scaffold coordinates so many ubiquitin events unresolved","Single-lab mechanistic studies"]},{"year":2015,"claim":"Defined the p75NTR ICD–NRAGE–NEDD9 axis as a Rac1-activating, cell-spreading module distinct from the apoptotic pathway.","evidence":"COS7 bioassay, cleavage inhibitors, yeast two-hybrid for NEDD9, Co-IP, Rac1 activation and dominant-negative constructs","pmids":["25472715"],"confidence":"Medium","gaps":["In vivo relevance untested","Reciprocal NEDD9 validation limited"]},{"year":2016,"claim":"Added a DNA-repair function, showing NRAGE stabilizes RNF8/BARD1 and is required for efficient homologous recombination.","evidence":"Ternary complex Co-IP, ubiquitination and HRR reporter assays, knockdown sensitivity and xenograft","pmids":["27035619"],"confidence":"Medium","gaps":["Nuclear localization control during DDR unclear","Single-lab study"]},{"year":2016,"claim":"Showed selective positive regulation of a subset of bHLH-PAS transcription factors via cytoplasmic interaction with nascent proteins, refining MAGED1's transcriptional-chaperone role.","evidence":"Co-IP, reporter assays, subcellular localization","pmids":["27472814"],"confidence":"Medium","gaps":["Basis of partner selectivity unresolved","In vivo significance untested"]},{"year":2017,"claim":"Linked MAGED1 to osteoblast differentiation and to Wnt suppression via β-catenin O-GlcNAcylation, extending its developmental and signaling reach.","evidence":"Co-IP, Runx2 reporter and differentiation assays; Xenopus axis duplication, O-GlcNAc detection and Co-IP","pmids":["28528976","28427939"],"confidence":"Medium","gaps":["Enzyme mediating β-catenin O-GlcNAcylation not identified","Single-lab studies"]},{"year":2018,"claim":"Established metabolic and addiction-related roles: MAGED1 destabilizes PPARγ to limit adiposity, inhibits NF-κB via IKKβ in odontogenesis, and is required in cortico-accumbal circuits for cocaine sensitization.","evidence":"Knockout mice with PPARγ stability/adipocyte assays; Co-IP/IKK-inhibitor differentiation assays; conditional cell-type-specific KO with electrophysiology and in vivo microdialysis","pmids":["30121577","29448842","30002119"],"confidence":"High","gaps":["Molecular link between MAGED1 and dopamine release not resolved","Cell-type specificity of metabolic roles unclear"]},{"year":2020,"claim":"Placed MAGED1 downstream of CDK4/6-E2F1 to promote FBP1 degradation and glycolysis in pancreatic cancer.","evidence":"CDK4/6 inhibitor, E2F1 reporter, FBP1 stability and glycolysis assays","pmids":["32987196"],"confidence":"Low","gaps":["No direct MAGED1-FBP1 interaction confirmed","Mechanism inferred from pharmacology and expression"]},{"year":2021,"claim":"Showed MAGED1 expression is itself controlled post-transcriptionally by m6A/YTHDF1-driven translation, with downstream PCNA-dependent proliferation in pulmonary hypertension.","evidence":"m6A-RIP-seq, RNA-IP, YTHDF1 and METTL3 knockout, genetic ablation, PCNA Western and proliferation assays","pmids":["33465322"],"confidence":"Medium","gaps":["Whether this regulation operates in other tissues unknown","Single-lab study"]},{"year":2023,"claim":"Defined MAGED1 as a USP7-partnering scaffold controlling H2A monoubiquitination in thalamic neurons to drive cocaine-adaptive behavior, providing an epigenetic mechanism for its addiction phenotype.","evidence":"Vglut2-Cre conditional knockout, USP7 inhibition, H2A monoUb ChIP, transcriptome and locomotor sensitization assays","pmids":["38123574"],"confidence":"High","gaps":["Genome-wide targets of the MAGED1-USP7 epigenetic activity not fully mapped","Reciprocal USP7 binding domain not defined"]},{"year":2026,"claim":"Connected MAGED1 dysfunction to disease, showing a frameshift variant disrupts Praja1 binding, stabilizes truncated protein, and abolishes anti-migratory function.","evidence":"Co-IP, immunofluorescence, Western blot, wound healing and cell cycle/apoptosis assays","pmids":["42162770"],"confidence":"Medium","gaps":["Specific disease and patient-level consequences not detailed here","Single-lab variant follow-up"]},{"year":null,"claim":"How a single scaffold selectively coordinates its many ubiquitin-, transcription-, and signaling partners in a context-specific manner, and the structural basis of its domain interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of domain-partner interactions","Mechanism determining which substrate/pathway is engaged in a given cell type is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,23]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[16,21,24,34]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,6,12,20,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,22,28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,25]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,24,34]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,7,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,14,23]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,6,12,20]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,16,21,22,28]}],"complexes":["TAK1-TAB1-XIAP complex","necdin-MAGED1-Msx ternary complex","RNF8-BARD1-NRAGE complex"],"partners":["P75NTR","XIAP","TAK1","PRAJA1","FBXO7","RORA","NEDD9","USP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5V3","full_name":"Melanoma-associated antigen D1","aliases":["MAGE tumor antigen CCF","MAGE-D1 antigen","Neurotrophin receptor-interacting MAGE homolog"],"length_aa":778,"mass_kda":86.2,"function":"Involved in the apoptotic response after nerve growth factor (NGF) binding in neuronal cells. Inhibits cell cycle progression, and facilitates NGFR-mediated apoptosis. May act as a regulator of the function of DLX family members. May enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. Plays a role in the circadian rhythm regulation. May act as RORA co-regulator, modulating the expression of core clock genes such as BMAL1 and NFIL3, induced, or NR1D1, repressed","subcellular_location":"Cytoplasm; Cell membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y5V3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAGED1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAGED1","total_profiled":1310},"omim":[{"mim_id":"300801","title":"CHROMOSOME Xp11.23-p11.22 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/300801"},{"mim_id":"300702","title":"MELANOMA ANTIGEN, FAMILY D, 4; MAGED4","url":"https://www.omim.org/entry/300702"},{"mim_id":"300470","title":"MELANOMA ANTIGEN, FAMILY D, 2; MAGED2","url":"https://www.omim.org/entry/300470"},{"mim_id":"300420","title":"PRAJA RING FINGER UBIQUITIN LIGASE 1; PJA1","url":"https://www.omim.org/entry/300420"},{"mim_id":"300224","title":"MELANOMA ANTIGEN, FAMILY D, 1; MAGED1","url":"https://www.omim.org/entry/300224"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAGED1"},"hgnc":{"alias_symbol":["NRAGE","DLXIN-1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5V3","domains":[{"cath_id":"1.10.10.1200","chopping":"466-547_706-741","consensus_level":"medium","plddt":76.9067,"start":466,"end":741},{"cath_id":"1.10.10.1210","chopping":"566-637","consensus_level":"medium","plddt":90.4328,"start":566,"end":637}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5V3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5V3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5V3-F1-predicted_aligned_error_v6.png","plddt_mean":50.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAGED1","jax_strain_url":"https://www.jax.org/strain/search?query=MAGED1"},"sequence":{"accession":"Q9Y5V3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5V3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5V3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5V3"}},"corpus_meta":[{"pmid":"10985348","id":"PMC_10985348","title":"NRAGE, 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and the radioresistance of esophageal carcinoma cell line TE13R120.","date":"2010","source":"Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20868560","citation_count":10,"is_preprint":false},{"pmid":"20595047","id":"PMC_20595047","title":"Dlxin-1, a MAGE family protein, induces accelerated neurite outgrowth and cell survival by enhanced and early activation of MEK and Akt signalling pathways in PC12 cells.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20595047","citation_count":10,"is_preprint":false},{"pmid":"27472814","id":"PMC_27472814","title":"MAGED1 is a novel regulator of a select subset of bHLH PAS transcription factors.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/27472814","citation_count":10,"is_preprint":false},{"pmid":"28414775","id":"PMC_28414775","title":"Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28414775","citation_count":10,"is_preprint":false},{"pmid":"19268530","id":"PMC_19268530","title":"NRAGE: a potential rheostat during branching morphogenesis.","date":"2009","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/19268530","citation_count":10,"is_preprint":false},{"pmid":"19937275","id":"PMC_19937275","title":"Mapping of NRAGE domains reveals clues to cell viability in BMP signaling.","date":"2010","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/19937275","citation_count":7,"is_preprint":false},{"pmid":"29448842","id":"PMC_29448842","title":"Knockdown of NRAGE induces odontogenic differentiation by activating NF-κB signaling in mouse odontoblast-like cells.","date":"2018","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/29448842","citation_count":6,"is_preprint":false},{"pmid":"35433476","id":"PMC_35433476","title":"NRAGE Confers Radiation Resistance in 2D and 3D Cell Culture and Poor Outcome in Patients With Esophageal Squamous Cell Carcinoma.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35433476","citation_count":6,"is_preprint":false},{"pmid":"26379857","id":"PMC_26379857","title":"The Effect of NRAGE on cell cycle and apoptosis of human dental pulp cells and MDPC-23.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26379857","citation_count":6,"is_preprint":false},{"pmid":"28639909","id":"PMC_28639909","title":"Silencing of NRAGE induces autophagy via AMPK/Ulk1/Atg13 signaling pathway in NSCLC cells.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28639909","citation_count":6,"is_preprint":false},{"pmid":"28427939","id":"PMC_28427939","title":"NRAGE induces β-catenin/Arm O-GlcNAcylation and negatively regulates Wnt signaling.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28427939","citation_count":4,"is_preprint":false},{"pmid":"31916845","id":"PMC_31916845","title":"Knockdown of NRAGE Impairs Homologous Recombination Repair and Sensitizes Hepatoblastoma Cells to Ionizing Radiation.","date":"2020","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/31916845","citation_count":4,"is_preprint":false},{"pmid":"30508943","id":"PMC_30508943","title":"NRAGE is a potential diagnostic biomarker of hepatocellular 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brain","url":"https://pubmed.ncbi.nlm.nih.gov/36774489","citation_count":2,"is_preprint":false},{"pmid":"39370811","id":"PMC_39370811","title":"Study of role of melanoma-associated antigen D1 (MAGE-D1) in hepatocellular carcinoma.","date":"2024","source":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research","url":"https://pubmed.ncbi.nlm.nih.gov/39370811","citation_count":1,"is_preprint":false},{"pmid":"40338441","id":"PMC_40338441","title":"miR-2400 promotes proliferation of bovine skeletal muscle-derived satellite cells by regulating MAGED1 genes expression.","date":"2025","source":"Journal of muscle research and cell motility","url":"https://pubmed.ncbi.nlm.nih.gov/40338441","citation_count":0,"is_preprint":false},{"pmid":"42162770","id":"PMC_42162770","title":"De novo variants in MAGED1 suggest a role in intellectual disability pathogenesis.","date":"2026","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/42162770","citation_count":0,"is_preprint":false},{"pmid":"34755671","id":"PMC_34755671","title":"[Mage-D1 binding to activated p75NTR positively regulates mineralization of rat ectomesenchymal stem cells in vitro].","date":"2021","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/34755671","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31724,"output_tokens":8584,"usd":0.111966,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18469,"output_tokens":7105,"usd":0.134985,"stage2_stop_reason":"end_turn"},"total_usd":0.246951,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"NRAGE (MAGED1) directly binds the p75 neurotrophin receptor (p75NTR) intracellular domain in vitro and in vivo; this interaction is functionally exclusive with TrkA binding to p75NTR. NRAGE association with the plasma membrane occurs when NGF is bound to p75NTR, and NRAGE overexpression facilitates cell cycle arrest and NGF-dependent apoptosis in sympathetic neuron precursors.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, overexpression in sympathetic neuron precursor cells\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and in vitro binding with functional consequence (apoptosis), replicated by multiple subsequent studies\",\n      \"pmids\": [\"10985348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NRAGE-induced apoptosis proceeds through a JNK-dependent mitochondrial pathway: induced NRAGE expression activates JNK, causes cytosolic accumulation of cytochrome c, and activates caspases-3, -7, and -9; blocking JNK or dominant-negative c-Jun ablates NRAGE-mediated caspase activation and cell death.\",\n      \"method\": \"Inducible recombinant NRAGE adenovirus, pharmacological JNK inhibition, dominant-negative overexpression, cytochrome c fractionation, caspase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (pharmacological inhibition, dominant-negative, biochemical fractionation) in single rigorous study establishing the mechanistic pathway\",\n      \"pmids\": [\"12376548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGED1 (Dlxin-1) binds Dlx5, Dlx7, and Msx2 homeodomain proteins through its hexapeptide repeat domain, forms homomultimers in vivo, and activates Dlx5-dependent transcriptional function in reporter gene assays.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transfection/reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assay, replicated by multiple subsequent studies\",\n      \"pmids\": [\"11084035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The RING finger E3 ubiquitin ligase Praja1 binds the C-terminal necdin homology domain of MAGED1 (Dlxin-1) and promotes its ubiquitination and proteasome-dependent degradation, thereby down-regulating Dlx5-dependent transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, proteasome inhibitor rescue, RING-finger mutant, in vivo ubiquitination assay, reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding, in vivo ubiquitination assay with mutagenesis, proteasome inhibitor rescue, and functional reporter assay in one study\",\n      \"pmids\": [\"11959851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"UNC5H1 induces apoptosis through a direct interaction between its ZU-5 domain (plus adjacent PEST sequence) and NRAGE; chimeric UNC5H2/3 receptors engineered with this region gain NRAGE binding and increased apoptosis, and UNC5H1 fails to induce apoptosis in PC12 cells lacking endogenous NRAGE.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping with chimeric receptors, NRAGE knockdown/overexpression in PC12 cells, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping, chimeric receptor rescue, and loss/gain of function, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"12598531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ror2 (but not Ror1) associates with MAGED1 (Dlxin-1) via its cytoplasmic C-terminal proline/serine-threonine-rich region interacting with the necdin homology domain of Dlxin-1. This interaction sequesters Dlxin-1 in membranous compartments, preventing its nuclear localization, and thereby modulates Msx2 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, transient expression, immunohistochemistry, subcellular fractionation of Ror2−/− fibroblasts, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, knockout fibroblast fractionation, and functional reporter assay in one study\",\n      \"pmids\": [\"12754255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAGED1 directly interacts with necdin via its MAGE homology domain and with Msx1/Msx2 via its hexapeptide repeat domain, forming a ternary complex that releases Msx-dependent transcriptional repression and promotes myogenic differentiation of C2C12 cells.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, endogenous complex detection in differentiating cells, transcriptional reporter assay, stable transfection + differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ternary complex reconstituted in vitro and detected endogenously, with functional differentiation assay\",\n      \"pmids\": [\"15272023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NRAGE is a mandatory component of the non-canonical BMP signaling cascade: NRAGE binds and functions with the TAK1-TAB1-XIAP complex to activate p38 MAPK and induce apoptosis in neural progenitors; disruption of NRAGE blocks p38 activation independently of Smad signaling.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative constructs, siRNA knockdown, p38 phosphorylation assays, apoptosis assays in neural progenitors\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function approaches with defined biochemical readouts, replicated by subsequent studies\",\n      \"pmids\": [\"16107717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BRCA2 binds and stabilizes MAGED1 protein; expression of BRCA2 and MAGED1 synergistically suppresses cell proliferation independently of the p53 pathway, and MAGED1 expression is required for BRCA2-mediated growth suppression.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of MAGED1, cell proliferation assays in multiple cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RNAi epistasis, single lab with two orthogonal methods\",\n      \"pmids\": [\"15930293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cytosolic PrP(C) constructs interact directly with NRAGE (identified by yeast two-hybrid, confirmed by in vitro binding and co-immunoprecipitation); co-expression of NRAGE and cytosolic PrP affects mitochondrial membrane potential, and NRAGE accumulates in perinuclear aggresomes upon proteasome inhibition.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, subcellular localization (co-localization in aggresomes), mitochondrial membrane potential assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding confirmations plus functional mitochondrial readout, single lab\",\n      \"pmids\": [\"15911347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NRAGE interacts with the anti-apoptotic factor Che-1/AATF and sequesters it in the cytoplasm, preventing nuclear localization; NRAGE overexpression promotes proteasome-dependent degradation of Che-1, and Che-1 overexpression completely reverts NRAGE-induced cell death.\",\n      \"method\": \"Co-immunoprecipitation, EGFP-NRAGE subcellular localization, proteasome inhibitor assay, overexpression rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, localization, proteasome rescue, and functional rescue, single lab with multiple methods\",\n      \"pmids\": [\"17488777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NRAGE is required in vivo for developmental apoptosis: NRAGE knockout mice have defects in sympathetic neuron apoptosis similar to p75NTR knockouts, show attenuated BDNF-dependent JNK activation, exhibit identical hair follicle catagen defects as p75NTR knockouts, and display additional motoneuron apoptosis defects not seen in p75NTR knockouts.\",\n      \"method\": \"NRAGE knockout mouse generation, histological apoptosis quantification, primary sympathetic neuron culture, JNK activation assay, hair follicle analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple in vivo and in vitro mechanistic readouts, co-expression and phenocopy evidence with p75NTR KO\",\n      \"pmids\": [\"18772898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAGED1 binds RORα and regulates circadian clock gene expression (Bmal1, Rev-erbα, E4bp4) through RORE elements; Maged1 knockout mice show shortened circadian period and altered rest-activity bouts, demonstrating MAGED1 is required for robustness of the molecular clock.\",\n      \"method\": \"Genetic screen, Maged1 knockout mice behavioral analysis, in vitro and in vivo binding assays, reporter gene assays with RORE elements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout phenotype plus direct binding and reporter assay evidence in vivo and in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"20300063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NRAGE is a negative regulator of NGF-induced neurite outgrowth: NRAGE knockdown accelerates NGF-mediated neurite outgrowth and increases TrkA-ERK activation; NRAGE downregulates TrkA expression post-transcriptionally and blocks NGF-induced TrkA phosphorylation at tyrosine-490.\",\n      \"method\": \"RNAi knockdown, overexpression, MEK inhibitor treatment, TrkA phosphorylation assays, neurite outgrowth quantification in PC12 cells\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss/gain of function with defined biochemical (TrkA phosphorylation) and cellular (neurite outgrowth) readouts, single lab\",\n      \"pmids\": [\"20127820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NRAGE acts via the XIAP-TAK1-TAB1 complex to activate IKK-α/β phosphorylation and NF-κB transcriptional activation in the non-canonical BMP pathway; siRNA ablation of NRAGE inhibits NF-κB activation, and ablation of TAK1/TAB1 blocks NRAGE-induced NF-κB activation.\",\n      \"method\": \"siRNA knockdown, morpholino knockdown, IKK phosphorylation assay, NF-κB luciferase reporter assay, cytokine profiling\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double knockdown, reporter assay, single lab multiple methods\",\n      \"pmids\": [\"20100315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NRAGE's unique hexapeptide repeat domain directly interacts with XIAP (demonstrated by FRET), and this domain is responsible for downstream NF-κB activation and IKK subunit phosphorylation in BMP signaling; a peptide modeled after this repeat domain inhibits NF-κB activation and apoptosis in P19 cells.\",\n      \"method\": \"FRET, deletion mutagenesis, p38 phosphorylation assay, caspase-3 cleavage assay, NF-κB reporter assay, peptide inhibitor\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET for direct interaction, domain mapping by deletion, functional assays, single lab\",\n      \"pmids\": [\"21789165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAGED1 binds SERT (serotonin transporter) via its necdin homology domain and promotes SERT ubiquitylation; MAGED1 knockout mice show hypoactive serotonergic function with hyperexpression of SERT due to decreased ubiquitylation, and MAGED1 overexpression decreases SERT protein level and serotonin uptake activity.\",\n      \"method\": \"Co-immunoprecipitation, MAGED1 knockout mice, siRNA knockdown, ubiquitylation assays, serotonin uptake assays, Western blot\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse, in vitro ubiquitylation, domain-mapped binding, and functional serotonin uptake assay, multiple orthogonal methods\",\n      \"pmids\": [\"22457503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of Maged1 severely reduces mature oxytocin levels in the hypothalamus without reducing precursor levels, indicating MAGED1 is required for OT processing or stability; oxytocin administration rescues social memory deficits in Maged1 knockout mice.\",\n      \"method\": \"Maged1 knockout mice, RIA/ELISA for oxytocin and precursors, OT rescue experiment, behavioral assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with peptide-level biochemistry and pharmacological rescue, single lab\",\n      \"pmids\": [\"22865874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NRAGE blocks the Ror2-Src interaction and inhibits Ror2-mediated cell migration by decreasing Src and focal adhesion kinase (FAK) activity; NRAGE sharply blocks the interaction between Src SH1 domain and the C-terminus of Ror2.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, overexpression/knockdown, migration assay in B16/B16-BL6 cells\",\n      \"journal\": \"Cancer genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex, kinase activity assay, and functional migration assay, single lab\",\n      \"pmids\": [\"23142633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The ubiquitin ligase Praja1 co-localizes with NRAGE and reduces NRAGE levels via proteasome-dependent degradation; Praja1 overexpression suppresses NGF-induced neurite formation in PC12 cells through NRAGE degradation.\",\n      \"method\": \"Co-localization (immunofluorescence), Western blot, proteasome inhibitor rescue, stable overexpression in PC12 cells, neurite assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteasome inhibitor rescue plus functional neurite assay, single lab\",\n      \"pmids\": [\"23717400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAGED1 co-interacts with CREB through its hexapeptide repeat domain; Maged1 knockout reduces CREB-dependent transcription and BDNF levels, and is associated with impaired long-term potentiation and spatial learning.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, LTP electrophysiology, Maged1 knockout mice, Western blot\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and reporter assay plus KO phenotype, single lab\",\n      \"pmids\": [\"24700102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NRAGE physically interacts with PCNA via DNA polymerase III subunit and stabilizes PCNA by reducing K48-linked polyubiquitination; knockdown of NRAGE promotes PCNA proteasomal degradation via USP10 regulation, and PCNA overexpression rescues growth inhibition in NRAGE-deficient esophageal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, USP10 identification, cell growth/cycle assays, rescue by PCNA overexpression, in vivo xenograft\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and rescue experiment, single lab\",\n      \"pmids\": [\"24710624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBXO7 interacts with NRAGE and mediates Lys-63-linked (non-degradative) polyubiquitination of NRAGE; this promotes formation of the NRAGE-TAK1-TAB1 and BMP receptor-NRAGE-TAK1-TAB1 complexes and upregulates NF-κB activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, K63-linked ubiquitination assay, FBXO7 knockdown/overexpression, NF-κB reporter assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, and reporter assay, single lab\",\n      \"pmids\": [\"24947323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"p75NTR-dependent Rac1 activation requires proteolytic cleavage of p75NTR (by ADAM17 and γ-secretase) to generate the intracellular domain (ICD), and the ICD signals through NRAGE and a newly identified NRAGE-binding partner NEDD9 to activate Rac1 and promote cell spreading.\",\n      \"method\": \"Bioassay in COS7 cells, pharmacological cleavage inhibitors, yeast two-hybrid for NEDD9, co-immunoprecipitation, Rac1 activation assay, dominant-negative constructs\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel interaction by yeast two-hybrid confirmed by Co-IP, epistasis by pharmacological and dominant-negative approaches, single lab\",\n      \"pmids\": [\"25472715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NRAGE is required for efficient homologous recombination repair of double-strand breaks; NRAGE regulates stability of RNF8 and BARD1 via ubiquitin-proteolytic pathway and forms a ternary complex with RNF8 and BARD1 (via their RING domains), facilitating their interaction and DDR.\",\n      \"method\": \"Co-immunoprecipitation (ternary complex), ubiquitination assay, HRR reporter assay, knockdown with DNA damage sensitivity assays in vitro and in vivo xenograft\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ternary complex Co-IP, ubiquitin assay, and functional HRR assay, single lab\",\n      \"pmids\": [\"27035619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAGED1 binds and positively regulates a select subset of bHLH PAS transcription factors (SIM1, SIM2, NPAS4, ARNT2) but not others (AhR, HIF1α, ARNT); interaction is mediated by PAS repeat regions and MAGED1 appears to interact with nascent bHLH PAS proteins in the cytoplasm to enhance their function prior to nuclear import, without affecting their protein levels.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assay, subcellular localization analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective binding confirmed by Co-IP with reporter assay, subcellular localization, single lab\",\n      \"pmids\": [\"27472814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Necdin promotes osteoblast differentiation through formation of a complex with MAGED1 and Dlx5, and activation of Runx2 promoter; co-expression of necdin and MAGED1 is required to achieve osteoblast-specific marker induction.\",\n      \"method\": \"Co-immunoprecipitation, stable transfection, osteoblast differentiation assay, Runx2 reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating ternary complex, reporter assay, differentiation assay, single lab\",\n      \"pmids\": [\"28528976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NRAGE induces O-GlcNAcylation of β-catenin/Arm, which causes failure of the association between β-catenin and pygopus (required for Wnt target gene transcription), thereby suppressing Wnt pathway output despite promoting β-catenin nuclear localization.\",\n      \"method\": \"Reporter assay, RNAi, Xenopus axis duplication assay, O-GlcNAc modification detection, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Xenopus assay, post-translational modification detection, Co-IP, multiple methods but single lab\",\n      \"pmids\": [\"28427939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MAGED1 binds PPARγ and suppresses its stability and transcriptional activity; MAGED1-deficient mice show increased PPARγ protein levels, more adipocyte precursors, and hyperplasia of white adipose tissue, with improved insulin sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, MAGED1 knockout mice, PPARγ stability assay, target gene expression, adipocyte differentiation assay\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus knockout mouse with biochemical and cellular readouts, single lab\",\n      \"pmids\": [\"30121577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Maged1 is critical for cortico-accumbal neurotransmission and cocaine-induced dopamine release in the nucleus accumbens; expression of Maged1 in the prefrontal cortex and amygdala (but not in dopaminergic or striatal GABAergic neurons) is required for cocaine-mediated behavioral sensitization.\",\n      \"method\": \"Maged1 knockout mice, conditional knockout (cell-type specific), electrophysiology in brain slices, in vivo microdialysis, conditioned place preference, drug self-administration\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-type specificity, electrophysiology, and in vivo dopamine measurement, multiple orthogonal methods\",\n      \"pmids\": [\"30002119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Maged1 deficiency results in reduced p21CIP1/WAF1 levels, defective cell cycle exit, and impaired myotube maturation during myoblast differentiation; in vivo this causes delayed muscle regeneration after injury.\",\n      \"method\": \"Maged1 knockout mice, in vitro myoblast differentiation, p21 Western blot, cell cycle analysis, in vivo muscle injury model\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with defined molecular (p21) and cellular (differentiation, regeneration) readouts, single lab\",\n      \"pmids\": [\"20646279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NRAGE binds IKKβ (co-immunoprecipitation) and inhibits the NF-κB signaling pathway; NRAGE knockdown promotes odontogenic differentiation through increased NF-κB1 nuclear translocation and p65 phosphorylation, effects reversed by an IKK inhibitor.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, lentivirus-mediated shRNA knockdown, IKK inhibitor, differentiation assays\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying IKKβ as binding partner, pharmacological rescue, and functional differentiation assay, single lab\",\n      \"pmids\": [\"29448842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CDK4/6-E2F1 signaling axis increases MAGED1 expression, which in turn promotes FBP1 degradation and aerobic glycolysis (Warburg effect) in pancreatic cancer; CDK4/6 inhibitor PD0332991 stabilizes FBP1 by repressing MAGED1 expression.\",\n      \"method\": \"CDK4/6 inhibitor treatment, E2F1 reporter assay, FBP1 stability assay, glycolysis measurements\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological and expression data, mechanism inferred without direct protein-protein interaction confirmation, single lab\",\n      \"pmids\": [\"32987196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 recognizes m6A-modified MAGED1 mRNA and promotes its translation in an m6A-dependent manner (absent in METTL3-deficient cells); increased MAGED1 protein promotes PASMC proliferation through PCNA upregulation and contributes to pulmonary hypertension.\",\n      \"method\": \"m6A-RIP sequencing, RNA immunoprecipitation, YTHDF1 knockout mice, MAGED1 genetic ablation, METTL3 knockout, PCNA Western blot, proliferation assays\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP, METTL3-KO mechanistic control, and genetic ablation with defined molecular readout (PCNA), single lab\",\n      \"pmids\": [\"33465322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Maged1 acts as a scaffold that partners with USP7 to regulate H2A monoubiquitination in paraventricular thalamus (PVT) neurons; chronic cocaine use increases H2A monoubiquitination in PVT, and Maged1-specific inactivation in thalamic Vglut2 neurons or USP7 inhibition blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization.\",\n      \"method\": \"Conditional Maged1 knockout (Vglut2-Cre), USP7 pharmacological inhibition, H2A monoubiquitination ChIP, locomotor sensitization behavioral assay, transcriptome analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cell-type-specific KO, ChIP for epigenetic mark, pharmacological inhibition, and behavioral assay, multiple orthogonal methods\",\n      \"pmids\": [\"38123574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A frameshift variant in MAGED1 (Leu137PhefsTer4) disrupts the interaction between MAGED1 and the E3 ubiquitin ligase Praja-1 (co-immunoprecipitation), impairs degradation of the truncated protein leading to its abnormal stabilization, and abolishes MAGED1's inhibitory effect on cell migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blot, wound healing assay, cell cycle/apoptosis assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction disruption, protein stability assay, and functional migration assay, single lab with variant-specific mechanistic follow-up\",\n      \"pmids\": [\"42162770\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGED1 (NRAGE/Dlxin-1) is a multifunctional scaffold/adaptor protein that operates at the intersection of several signaling pathways: it directly binds p75NTR and blocks its association with TrkA to facilitate NGF-dependent apoptosis via a JNK-mitochondrial-caspase cascade; it engages the TAK1-TAB1-XIAP complex downstream of BMP receptors to activate p38 MAPK and NF-κB; it binds Dlx/Msx homeodomain transcription factors through its hexapeptide repeat domain to modulate transcription; it serves as an adaptor for E3 ubiquitin ligases (Praja1, FBXO7) that control its own stability and the stability of substrates including SERT, PCNA, Che-1/AATF, and PPARγ; it interacts with RORα to regulate circadian clock gene expression; in neurons it partners with NEDD9 downstream of the p75NTR intracellular domain to activate Rac1; and in the paraventricular thalamus it partners with USP7 to regulate H2A monoubiquitination and cocaine-adaptive behaviors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAGED1 (NRAGE/Dlxin-1) is a multifunctional scaffold/adaptor protein that integrates neurotrophin, BMP, transcription-factor and ubiquitin signaling to control developmental apoptosis, differentiation and neural function [#0, #7, #11]. In the neurotrophin axis it binds the p75NTR intracellular domain in a manner mutually exclusive with TrkA and drives NGF-dependent apoptosis through a JNK–mitochondrial–caspase cascade, a function genetically required in vivo where NRAGE-null mice phenocopy p75NTR knockouts in sympathetic neuron and hair-follicle apoptosis [#0, #1, #11]. The same membrane-proximal signaling also generates a p75NTR ICD that, with the NRAGE partner NEDD9, activates Rac1, while NRAGE conversely restrains TrkA-ERK signaling and neurite outgrowth [#23, #13]. In non-canonical BMP signaling NRAGE is an obligatory component that engages the TAK1–TAB1–XIAP complex via its hexapeptide repeat domain to activate p38 MAPK and IKK/NF-\\u03baB [#7, #14, #15]. Through that hexapeptide repeat and a necdin-homology domain it binds Dlx/Msx homeodomain factors and necdin to form ternary complexes that relieve Msx repression and promote myogenic and osteogenic differentiation [#2, #6, #26]. NRAGE further acts as an adaptor coupling substrates to the ubiquitin system: it is itself degraded by the RING E3 ligase Praja1 and receives K63 ubiquitination from FBXO7, and it controls the stability or modification of SERT, PCNA, Che-1/AATF, PPAR\\u03b3, RNF8/BARD1 and H2A [#3, #22, #16, #21, #10, #28, #24, #34]. It binds ROR\\u03b1 to sustain robustness of the circadian clock and partners with USP7 in paraventricular thalamus neurons to regulate H2A monoubiquitination and cocaine-adaptive behavior [#12, #34, #29]. A frameshift variant (Leu137PhefsTer4) that abolishes Praja1-dependent degradation and the protein's anti-migratory function links MAGED1 dysfunction to disease [#35].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established MAGED1's founding role as a death-promoting adaptor by showing it binds the p75NTR intracellular domain in competition with TrkA, linking a receptor to an apoptotic outcome.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding and Co-IP with overexpression in sympathetic neuron precursors\",\n      \"pmids\": [\"10985348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the downstream death machinery\", \"Did not resolve which domain mediates p75NTR binding\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined a parallel transcriptional function by showing MAGED1 binds Dlx/Msx homeodomain factors through its hexapeptide repeat and modulates their activity.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, reporter gene assays\",\n      \"pmids\": [\"11084035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect transcriptional and apoptotic roles\", \"In vivo developmental relevance untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the apoptotic cascade downstream of NRAGE as a JNK-dependent mitochondrial-caspase pathway, converting the binding observation into a defined mechanism.\",\n      \"evidence\": \"Inducible NRAGE adenovirus, JNK inhibition, dominant-negative c-Jun, cytochrome c fractionation, caspase assays\",\n      \"pmids\": [\"12376548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NRAGE activates JNK was not identified\", \"Did not test requirement in vivo\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the first regulator of NRAGE stability, showing Praja1 ubiquitinates and degrades it to down-regulate Dlx5-dependent transcription.\",\n      \"evidence\": \"GST pulldown, Co-IP, in vivo ubiquitination, RING mutant, proteasome rescue, reporter assay\",\n      \"pmids\": [\"11959851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of degradation not defined\", \"Other E3 ligases not excluded\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Broadened NRAGE's death-receptor partners beyond p75NTR and defined a Ror2-dependent sequestration mechanism controlling its subcellular distribution and transcriptional output.\",\n      \"evidence\": \"Co-IP, domain mapping with chimeric UNC5H receptors, knockdown in PC12 cells, knockout fibroblast fractionation, reporter assays\",\n      \"pmids\": [\"12598531\", \"12754255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not unify nuclear vs membrane localization control\", \"Crosstalk between receptor partners untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed MAGED1 nucleates a necdin–Msx ternary complex that relieves transcriptional repression and promotes myogenic differentiation, defining a domain-resolved adaptor logic.\",\n      \"evidence\": \"In vitro binding, endogenous complex detection, reporter and differentiation assays in C2C12 cells\",\n      \"pmids\": [\"15272023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo myogenic requirement not shown here\", \"Did not address other homeodomain partners\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established NRAGE as a mandatory, Smad-independent component of non-canonical BMP signaling by linking it to the TAK1-TAB1-XIAP module driving p38 activation.\",\n      \"evidence\": \"Co-IP, dominant-negative and siRNA loss-of-function, p38 phosphorylation and apoptosis assays in neural progenitors\",\n      \"pmids\": [\"16107717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct XIAP-binding domain not yet mapped\", \"Receptor-level recruitment unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended NRAGE's interactome to growth-suppression (BRCA2) and to a cytosolic prion-protein/mitochondrial axis, hinting at broader regulatory roles.\",\n      \"evidence\": \"Co-IP, RNAi epistasis, proliferation assays; yeast two-hybrid, in vitro binding and mitochondrial membrane potential assays\",\n      \"pmids\": [\"15930293\", \"15911347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab observations\", \"Mechanism linking these partners to apoptosis unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed NRAGE drives death partly by cytoplasmic sequestration and proteasomal degradation of the anti-apoptotic factor Che-1/AATF.\",\n      \"evidence\": \"Co-IP, EGFP localization, proteasome inhibitor and overexpression rescue\",\n      \"pmids\": [\"17488777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for Che-1 not identified\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided genetic proof that NRAGE is required in vivo for developmental apoptosis, phenocopying and extending p75NTR knockout phenotypes.\",\n      \"evidence\": \"NRAGE knockout mice, apoptosis quantification, primary neuron culture, JNK assays, hair follicle analysis\",\n      \"pmids\": [\"18772898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Motoneuron-specific p75NTR-independent mechanism unresolved\", \"Did not address non-apoptotic roles\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Diversified MAGED1's physiology into circadian, neurotrophic-outgrowth, NF-\\u03baB and myogenic regulation, showing it tunes diverse transcriptional and signaling outputs.\",\n      \"evidence\": \"Maged1 knockout behavioral analysis with ROR\\u03b1 binding/reporter assays; RNAi/overexpression of TrkA signaling; XIAP-TAK1-TAB1/IKK NF-\\u03baB assays; knockout myoblast differentiation with p21 readout\",\n      \"pmids\": [\"20300063\", \"20127820\", \"20100315\", \"20646279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions of each role not separated\", \"Direct vs indirect transcriptional effects mixed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped the unique hexapeptide repeat domain as the direct XIAP-binding and NF-\\u03baB-activating module, enabling a peptide inhibitor of the pathway.\",\n      \"evidence\": \"FRET, deletion mutagenesis, p38/caspase/NF-\\u03baB assays, peptide inhibitor in P19 cells\",\n      \"pmids\": [\"21789165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the interaction unresolved\", \"Single-lab functional readouts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined MAGED1 as a substrate-targeting adaptor for ubiquitylation of SERT and as required for oxytocin maturation, linking it to monoaminergic and neuropeptide systems and behavior.\",\n      \"evidence\": \"Knockout mice with ubiquitylation/serotonin uptake assays; oxytocin RIA/ELISA and OT rescue with behavior\",\n      \"pmids\": [\"22457503\", \"22865874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase partnering MAGED1 on SERT not defined\", \"Mechanism of oxytocin processing role unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed NRAGE restrains Ror2-Src-FAK signaling to inhibit cell migration, adding a cytoskeletal/motility arm to its functions.\",\n      \"evidence\": \"Co-IP of ternary complex, kinase activity and migration assays in B16 cells\",\n      \"pmids\": [\"23142633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo metastasis relevance untested\", \"Direct vs scaffold-mediated Src inhibition unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected Praja1-mediated NRAGE degradation to a cellular output, showing it controls NGF-induced neurite formation.\",\n      \"evidence\": \"Co-localization, proteasome rescue, stable overexpression and neurite assays in PC12 cells\",\n      \"pmids\": [\"23717400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal regulating Praja1 activity unknown\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded MAGED1's ubiquitin-adaptor and transcriptional repertoire, linking it to PCNA stabilization, CREB-dependent transcription/synaptic plasticity, and FBXO7-mediated K63 ubiquitination that builds the BMP signaling complex.\",\n      \"evidence\": \"Co-IP/ubiquitination/USP10 and rescue assays for PCNA; Co-IP/ChIP/reporter with KO LTP for CREB; yeast two-hybrid, K63-linked ubiquitination and NF-\\u03baB reporter for FBXO7\",\n      \"pmids\": [\"24710624\", \"24700102\", \"24947323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a single scaffold coordinates so many ubiquitin events unresolved\", \"Single-lab mechanistic studies\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the p75NTR ICD–NRAGE–NEDD9 axis as a Rac1-activating, cell-spreading module distinct from the apoptotic pathway.\",\n      \"evidence\": \"COS7 bioassay, cleavage inhibitors, yeast two-hybrid for NEDD9, Co-IP, Rac1 activation and dominant-negative constructs\",\n      \"pmids\": [\"25472715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance untested\", \"Reciprocal NEDD9 validation limited\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Added a DNA-repair function, showing NRAGE stabilizes RNF8/BARD1 and is required for efficient homologous recombination.\",\n      \"evidence\": \"Ternary complex Co-IP, ubiquitination and HRR reporter assays, knockdown sensitivity and xenograft\",\n      \"pmids\": [\"27035619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear localization control during DDR unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed selective positive regulation of a subset of bHLH-PAS transcription factors via cytoplasmic interaction with nascent proteins, refining MAGED1's transcriptional-chaperone role.\",\n      \"evidence\": \"Co-IP, reporter assays, subcellular localization\",\n      \"pmids\": [\"27472814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of partner selectivity unresolved\", \"In vivo significance untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked MAGED1 to osteoblast differentiation and to Wnt suppression via \\u03b2-catenin O-GlcNAcylation, extending its developmental and signaling reach.\",\n      \"evidence\": \"Co-IP, Runx2 reporter and differentiation assays; Xenopus axis duplication, O-GlcNAc detection and Co-IP\",\n      \"pmids\": [\"28528976\", \"28427939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme mediating \\u03b2-catenin O-GlcNAcylation not identified\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established metabolic and addiction-related roles: MAGED1 destabilizes PPAR\\u03b3 to limit adiposity, inhibits NF-\\u03baB via IKK\\u03b2 in odontogenesis, and is required in cortico-accumbal circuits for cocaine sensitization.\",\n      \"evidence\": \"Knockout mice with PPAR\\u03b3 stability/adipocyte assays; Co-IP/IKK-inhibitor differentiation assays; conditional cell-type-specific KO with electrophysiology and in vivo microdialysis\",\n      \"pmids\": [\"30121577\", \"29448842\", \"30002119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between MAGED1 and dopamine release not resolved\", \"Cell-type specificity of metabolic roles unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed MAGED1 downstream of CDK4/6-E2F1 to promote FBP1 degradation and glycolysis in pancreatic cancer.\",\n      \"evidence\": \"CDK4/6 inhibitor, E2F1 reporter, FBP1 stability and glycolysis assays\",\n      \"pmids\": [\"32987196\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct MAGED1-FBP1 interaction confirmed\", \"Mechanism inferred from pharmacology and expression\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed MAGED1 expression is itself controlled post-transcriptionally by m6A/YTHDF1-driven translation, with downstream PCNA-dependent proliferation in pulmonary hypertension.\",\n      \"evidence\": \"m6A-RIP-seq, RNA-IP, YTHDF1 and METTL3 knockout, genetic ablation, PCNA Western and proliferation assays\",\n      \"pmids\": [\"33465322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this regulation operates in other tissues unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined MAGED1 as a USP7-partnering scaffold controlling H2A monoubiquitination in thalamic neurons to drive cocaine-adaptive behavior, providing an epigenetic mechanism for its addiction phenotype.\",\n      \"evidence\": \"Vglut2-Cre conditional knockout, USP7 inhibition, H2A monoUb ChIP, transcriptome and locomotor sensitization assays\",\n      \"pmids\": [\"38123574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide targets of the MAGED1-USP7 epigenetic activity not fully mapped\", \"Reciprocal USP7 binding domain not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected MAGED1 dysfunction to disease, showing a frameshift variant disrupts Praja1 binding, stabilizes truncated protein, and abolishes anti-migratory function.\",\n      \"evidence\": \"Co-IP, immunofluorescence, Western blot, wound healing and cell cycle/apoptosis assays\",\n      \"pmids\": [\"42162770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific disease and patient-level consequences not detailed here\", \"Single-lab variant follow-up\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold selectively coordinates its many ubiquitin-, transcription-, and signaling partners in a context-specific manner, and the structural basis of its domain interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of domain-partner interactions\", \"Mechanism determining which substrate/pathway is engaged in a given cell type is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 23]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [16, 21, 24, 34]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 6, 12, 20, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 22, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 25]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 24, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 7, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 14, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 6, 12, 20]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 16, 21, 22, 28]}\n    ],\n    \"complexes\": [\n      \"TAK1-TAB1-XIAP complex\",\n      \"necdin-MAGED1-Msx ternary complex\",\n      \"RNF8-BARD1-NRAGE complex\"\n    ],\n    \"partners\": [\n      \"p75NTR\",\n      \"XIAP\",\n      \"TAK1\",\n      \"Praja1\",\n      \"FBXO7\",\n      \"RORA\",\n      \"NEDD9\",\n      \"USP7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}