{"gene":"NR4A1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2004,"finding":"Nur77 (NR4A1) directly interacts with the N-terminal loop region of Bcl-2 at the mitochondria, inducing a conformational change in Bcl-2 that exposes its BH3 domain and converts Bcl-2 from an anti-apoptotic to a pro-apoptotic protein, triggering cytochrome c release and apoptosis.","method":"Co-immunoprecipitation, domain mapping, mitochondrial fractionation, confocal microscopy, functional apoptosis assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP, domain mutagenesis, multiple orthogonal functional assays; highly cited foundational study","pmids":["14980220"],"is_preprint":false},{"year":1994,"finding":"Nur77 is required for activation-induced apoptosis in T-cell hybridomas; a dominant-negative Nur77 blocks TCR-induced cell death, establishing Nur77 as a necessary mediator of this pathway.","method":"Dominant-negative overexpression, gel shift analysis (EMSA), subtractive hybridization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — dominant-negative epistasis with defined phenotypic readout; highly cited foundational study replicated in subsequent work","pmids":["8121493"],"is_preprint":false},{"year":2001,"finding":"Akt physically interacts with Nur77 and phosphorylates it at Ser-350 within its DNA-binding domain in a PI3K-dependent manner, reducing Nur77 transcriptional activity by 50–85%.","method":"Co-immunoprecipitation, in vitro kinase assay, in vivo phosphorylation assay, luciferase reporter assay, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus in vivo validation and mutagenesis; multiple orthogonal methods","pmids":["11274386"],"is_preprint":false},{"year":1993,"finding":"Nur77 transactivation activity resides in its N-terminal domain; the C-terminal domain regulates this activity. Deletion of the domain immediately C-terminal to the zinc fingers abolishes DNA binding and nuclear localization. Nur77 is phosphorylated primarily at its N-terminal domain, and pp90rsk phosphorylates Ser-354 in vitro and in vivo.","method":"Deletion mapping, transactivation assays, in vitro phosphorylation with recombinant kinases, in vivo radiolabeling","journal":"Molecular Endocrinology","confidence":"High","confidence_rationale":"Tier 1 — systematic deletion mapping plus in vitro and in vivo phosphorylation assays","pmids":["8232315"],"is_preprint":false},{"year":2003,"finding":"TR3/Nur77 nuclear functions are controlled by subcellular localization: nuclear TR3 promotes cell proliferation via its DNA-binding and transactivation domains, while mitochondrial TR3 induces apoptosis independently of these domains. EGF/serum induces nuclear TR3 mitogenesis; MEKK1 activates JNK which phosphorylates TR3 and abolishes its DNA binding, blocking its mitogenic function.","method":"Confocal microscopy, siRNA knockdown, ectopic expression of TR3 mutants, BrdU incorporation, JNK kinase assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (live imaging, mutant analysis, siRNA, kinase assays) in a single study","pmids":["14612408"],"is_preprint":false},{"year":2012,"finding":"Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. Compound TMPA binds Nur77 with high affinity, releasing LKB1 to the cytoplasm where it phosphorylates AMPKα.","method":"Co-immunoprecipitation, subcellular fractionation, AMPK activity assays, compound binding assays, knockout mouse validation","journal":"Nature Chemical Biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, fractionation, functional rescue, in vivo knockout confirmation; multiple orthogonal methods","pmids":["22983157"],"is_preprint":false},{"year":2015,"finding":"Nur77 directly associates with the p65 subunit of NF-κB to block its binding to the κB element, suppressing inflammatory cytokine production. LPS-activated p38α phosphorylates Nur77, counteracting this NF-κB suppression.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assays, phosphorylation assays, compound screening","journal":"Nature Chemical Biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, phosphorylation assays, and in vivo sepsis model; multiple orthogonal methods","pmids":["25822914"],"is_preprint":false},{"year":1996,"finding":"Nur77/N10 transgenic thymocytes undergo apoptosis through upregulation of Fas ligand (FasL) expression; crossing to gld/gld mice (FasL-mutant) rescues the apoptosis phenotype, demonstrating Nur77-driven thymocyte apoptosis requires the Fas/FasL pathway.","method":"Transgenic mouse model, genetic epistasis with gld mutation, flow cytometry for thymocyte populations, FasL expression analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis in transgenic/mutant mice with defined cellular phenotype","pmids":["8643610"],"is_preprint":false},{"year":2011,"finding":"NR4A1 controls the differentiation and survival of Ly6C- (patrolling) monocytes in a cell-intrinsic manner; Nr4a1-/- mice lack patrolling monocytes, and residual Ly6C- cells in knockout bone marrow are arrested in S phase and undergo apoptosis.","method":"Knockout mouse analysis, bone marrow transplantation (chimera), flow cytometry, cell cycle analysis","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 — knockout plus BM chimera demonstrating cell-intrinsic requirement; multiple functional readouts","pmids":["21725321"],"is_preprint":false},{"year":2018,"finding":"Nur77 acts as an upstream transcriptional regulator of metabolic reprogramming in macrophages by downregulating isocitrate dehydrogenase (IDH) expression; Nur77-deficient macrophages accumulate higher succinate levels and produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner.","method":"Nr4a1-/- macrophages, metabolomics, IDH/SDH functional assays, cytokine measurements, atherosclerosis in vivo model","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with metabolomics and mechanistic epistasis; multiple orthogonal readouts","pmids":["30134173"],"is_preprint":false},{"year":2021,"finding":"Ubiquitinated mitochondrial Nur77 forms membraneless condensates through liquid-liquid phase separation; multivalent interaction between Nur77's N-terminal IDR and the PB1 domain of p62/SQSTM1, and between Nur77's UBA-interacting region and p62's UBA domain, coordinates sequestration of damaged mitochondria for mitophagy.","method":"Phase separation assays, co-immunoprecipitation, domain mutagenesis, live-cell imaging, mitophagy flux assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution of condensates, domain dissection, and functional mitophagy assays with mutagenesis","pmids":["34645818"],"is_preprint":false},{"year":2008,"finding":"Akt phosphorylates cytoplasmic Nur77 through physical interaction with its N-terminus, blocking Nur77 mitochondrial targeting and disrupting the Nur77–Bcl-2 interaction required for apoptosis induction.","method":"Co-immunoprecipitation, kinase assays, confocal microscopy, subcellular fractionation, insulin stimulation","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods showing Akt-Nur77 interaction, phosphorylation, and functional consequence on mitochondrial localization","pmids":["18713840"],"is_preprint":false},{"year":1997,"finding":"Glucocorticoid receptor (GR) antagonizes Nur77-dependent transcription at the NurRE element of the POMC gene by a mechanism similar to GR/AP-1 antagonism; GR also partly blunts CRH induction of Nur77 mRNA; in vitro binding and mutation analysis show GR antagonism of Nur77 does not require direct DNA binding by GR.","method":"Transfection/reporter assays, in vitro binding experiments, GR mutation analysis, Northern blotting","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding, mutagenesis, reporter assays in both endocrine and lymphoid cell contexts","pmids":["9315653"],"is_preprint":false},{"year":2006,"finding":"TR3/Nur77 translocates to the endoplasmic reticulum (ER) upon CD437 treatment, interacts with ER-associated Bcl-2, triggers early Ca²⁺ release from the ER, and induces apoptosis via ER-specific caspase-4 activation in parallel with mitochondrial stress and caspase-9 activation.","method":"Immunofluorescence, subcellular fractionation, co-immunoprecipitation, Ca²⁺ measurement, caspase activity assays","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods but single lab study","pmids":["17543302"],"is_preprint":false},{"year":2011,"finding":"TR3/Nur77 regulates mTORC1 signaling in lung cancer cells: it suppresses p53 (via a p300/TR3/Sp1 complex on GC-rich promoters including survivin), and in p53 wild-type cells, siTR3 activates p53 which induces sestrin2, activating AMPKα and inhibiting mTORC1.","method":"RNA interference, Western blot, ChIP, luciferase reporter assays, xenograft tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi + ChIP + reporter assays with in vivo validation; single lab","pmids":["22081070"],"is_preprint":false},{"year":2006,"finding":"TR3/Nur77 directly interacts with p53 (not MDM2), blocks p53 acetylation (reducing MDM2 transcription), and prevents MDM2-induced p53 ubiquitination, resulting in MDM2 ubiquitination and degradation; TR3 also enhances p53-mediated apoptosis by UV.","method":"Co-immunoprecipitation, GST pulldown, luciferase reporter, ubiquitination assay, acetylation assay","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 — GST pulldown, Co-IP, and multiple biochemical assays demonstrating mechanism; single lab but multiple orthogonal methods","pmids":["17139261"],"is_preprint":false},{"year":2003,"finding":"In colon cancer cells, butyrate- and NSAID-induced apoptosis involves nucleus-to-cytoplasm translocation of TR3/Nur77, with cytoplasmic (not direct mitochondrial) localization triggering BAX recruitment to mitochondria and cytochrome c release.","method":"GFP-TR3 live-cell imaging, TR3 mutant constructs, cytochrome c release assays, BAX co-localization","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging with functionally validated mutants; single lab","pmids":["14500374"],"is_preprint":false},{"year":2011,"finding":"TR3/Nur77 disrupts the association of β-catenin and TCF4 on chromatin and facilitates recruitment of transcriptional co-repressors to Wnt target gene promoters, suppressing Wnt signaling. GSK3β phosphorylates TR3, attenuating its inhibitory activity toward Wnt signaling in clinical colorectal cancers.","method":"ChIP, co-immunoprecipitation, reporter assays, knockout/transgenic mouse models, kinase assays on clinical samples","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — ChIP, Co-IP, kinase assays, in vivo Apc(min/+) mouse models; multiple orthogonal methods","pmids":["21873734"],"is_preprint":false},{"year":2012,"finding":"TR3/Nur77 forms a trimeric complex with TSC1/TSC2 that specifically promotes TSC2 degradation via the ubiquitin/proteasome pathway, activating mTORC1 (but not mTORC2) and leading to increased protein synthesis and cardiac hypertrophy in response to angiotensin II.","method":"Co-immunoprecipitation, proteasome inhibition, TR3 knockout/knockdown mouse models, mTORC1 activity assays","journal":"EMBO Molecular Medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of trimeric complex, in vivo knockout models, mechanistic pathway dissection; single lab but multiple methods","pmids":["23197407"],"is_preprint":false},{"year":2017,"finding":"NR4A1 is SUMOylated by SUMO2/3 at two specific sites; poly-SUMO modification targets NR4A1 for polyubiquitination by the SUMO-dependent E3 ligase RNF4 and subsequent proteasomal degradation. PIAS3 promotes SUMOylation and RNF4-mediated ubiquitination, while SENP1 de-conjugates SUMO; mutation of SUMO sites stabilizes NR4A1 and affects its regulation of NF-κB signaling.","method":"SUMOylation assays, ubiquitination assays, site-directed mutagenesis, PIAS3/SENP1 overexpression/knockdown, functional NF-κB reporter assays","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical SUMOylation/ubiquitination assays, mutagenesis of modification sites, functional validation; single lab but multiple orthogonal methods","pmids":["28622293"],"is_preprint":false},{"year":2011,"finding":"FHL2 physically interacts with Nur77 (identified by yeast two-hybrid and Co-IP); each of FHL2's four LIM domains binds Nur77, and both the N-terminal domain and DNA-binding domain of Nur77 are involved. FHL2 represses Nur77 transcriptional activity dose-dependently by inhibiting Nur77 binding to DNA, as shown by ChIP on the enolase3 promoter.","method":"Yeast two-hybrid, co-immunoprecipitation, domain mapping, ChIP, shRNA knockdown, reporter assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus Co-IP plus ChIP; multiple orthogonal methods","pmids":["22049082"],"is_preprint":false},{"year":2011,"finding":"TR3/Nur77 modulates vascular permeability by transcriptionally increasing endothelial nitric-oxide synthase expression and downregulating endothelial junction proteins; both effects require TR3 transcriptional activity (transactivation and DNA-binding domains).","method":"Nur77-/- mice, transgenic overexpression, dominant-negative TR3, in vivo vascular permeability assays, TR3 mutant analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic models (KO, transgenic, dominant-negative) plus domain mutant studies; multiple orthogonal approaches","pmids":["21730126"],"is_preprint":false},{"year":2006,"finding":"TR3/Nur77 angiogenic activity in endothelial cells (proliferation, survival, tube formation) operates through its transactivation and DNA-binding domains (transcriptional activity); overexpression promotes angiogenesis in vivo while antisense inhibits VEGF-A-induced angiogenesis.","method":"Antisense/overexpression in HUVECs, dominant-negative mutants, endothelial-selective retroviral targeting in vivo, Nur77-/- mice with tumor models","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 — TR3 mutant domain dissection, in vivo Nur77-/- tumor model, multiple orthogonal approaches","pmids":["16520388"],"is_preprint":false},{"year":2008,"finding":"PRMT1 physically interacts with TR3/Nur77 and stabilizes TR3 protein (delaying degradation), thereby enhancing TR3 DNA binding and transcriptional activity in a methyltransferase-independent manner. In turn, TR3 binding to the catalytic domain of PRMT1 inhibits PRMT1 methyltransferase activity, affecting STAT3 and Sam68 methylation.","method":"Co-immunoprecipitation, methyltransferase activity assays, protein stability assays, luciferase reporter assays, TR3 knockout mice with agonist","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, in vitro methyltransferase assays, and in vivo knockout validation; multiple orthogonal methods","pmids":["19095693"],"is_preprint":false},{"year":2011,"finding":"Pin1 binds phospho-Ser/Thr-Pro motifs on TR3 (at least three sites; key site Ser95-Pro), isomerizes them, stabilizes TR3 by retarding degradation, and enhances TR3 transactivation through phospho-Ser431 isomerization by ERK2. Pin1 also promotes TR3 targeting to the cyclin D2 promoter and recruitment of p300.","method":"Co-immunoprecipitation, in vitro Pin1 binding assays, protein stability assays, ChIP, proliferation/tumor growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — biochemical Pin1-substrate assays, stability analysis, ChIP; in vivo validation; multiple methods","pmids":["22002310"],"is_preprint":false},{"year":2006,"finding":"JNK phosphorylates TR3 specifically at Ser95 (mediated through MKK4/MKK7 → JNK1), inducing TR3 ubiquitination and degradation, abolishing its mitogenic activity, and blocking TR3 DNA binding and transactivation.","method":"In vitro kinase assays, site-directed mutagenesis (Ser95), ubiquitination assays, reporter assays, co-immunoprecipitation","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay with mutagenesis plus functional assays; single lab but multiple orthogonal methods","pmids":["17023523"],"is_preprint":false},{"year":2007,"finding":"TR3/Nur77 interacts with RXRα and blocks p300-induced acetylation of RXRα at Lys145 by sequestering RXRα from p300. 9-cis retinoic acid enhances TR3-RXRα association and promotes co-translocation from nucleus to mitochondria, inducing apoptosis.","method":"Co-immunoprecipitation, acetylation assays, luciferase reporter, subcellular fractionation, confocal microscopy","journal":"Molecular Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, biochemical acetylation assay, live-cell imaging; single lab","pmids":["17761950"],"is_preprint":false},{"year":2003,"finding":"PML physically interacts with the DNA-binding domain of Nur77 (amino acids 267–332; coiled-coil domain of PML) in vitro and in vivo, and represses Nur77 transcription by interfering with Nur77 DNA binding in a dose-dependent manner.","method":"GST pulldown, co-immunoprecipitation, EMSA, colocalization by confocal microscopy, domain mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — GST pulldown, Co-IP, and EMSA confirming mechanism; single lab","pmids":["12032831"],"is_preprint":false},{"year":2003,"finding":"NGFI-B/NR4A1 binds to two functional NBRE elements in the CYP11B2 (aldosterone synthase) promoter and transactivates CYP11B2 expression in adrenocortical cells; angiotensin II strongly induces NGFI-B and NURR1 protein, and calmodulin kinase partially mediates this induction.","method":"Transient transfection/reporter assays, EMSAs, promoter deletion/mutagenesis, Western blotting, kinase inhibition","journal":"Molecular Endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 — EMSA, promoter mutagenesis, and reporter assays; multiple orthogonal methods","pmids":["14645496"],"is_preprint":false},{"year":2015,"finding":"Nr4a1 directly suppresses Runx3 transcription in CD8+ T cells by recruiting the co-repressor CoREST to the Runx3 gene; loss of Nr4a1 increases Runx3 expression and causes a 2-fold increase in CD8+ T cell frequency.","method":"Nr4a1 knockout mice, ChIP (CoREST recruitment), RNA interference, flow cytometry","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct binding and co-repressor recruitment; KO mouse phenotype; single lab","pmids":["25762306"],"is_preprint":false},{"year":2018,"finding":"NR4A1 and NR4A3 directly bind a hematopoietic-specific Cebpa enhancer to activate Cebpa transcription, restricting HSC proliferation; they also occupy regulatory regions of NF-κB-regulated inflammatory cytokines to antagonize NF-κB signaling and maintain HSC quiescence.","method":"Conditional double-knockout mice, ChIP, gene expression profiling, NF-κB signaling assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — conditional KO plus ChIP with molecular profiling; multiple orthogonal methods","pmids":["29343483"],"is_preprint":false},{"year":2011,"finding":"NR4A1 deletion in macrophages enhances TLR4 signaling and increases phosphorylation of the p65 subunit of NF-κB, polarizing macrophages to a pro-inflammatory M1 phenotype; NF-κB inhibition blocks the excess activation of Nur77-/- macrophages.","method":"Nr4a1-/- chimeric mice, Western blot for p65 phosphorylation, NF-κB inhibitor experiments, cytokine measurement","journal":"Circulation Research","confidence":"Medium","confidence_rationale":"Tier 2 — knockout mouse with NF-κB epistasis; single lab","pmids":["22194622"],"is_preprint":false},{"year":2014,"finding":"Nr4a1 mediates the anti-inflammatory effects of apoptotic cell phagocytosis in macrophages; Nr4a1 deletion prevents inhibition of NF-κB signaling and IL-12 repression normally induced by apoptotic cells, demonstrating Nr4a1 is required for tolerance to dying-self signals.","method":"Nr4a1-/- macrophages, NF-κB reporter assay, IL-12 measurement, in vivo pristane-induced lupus model","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with NF-κB assays and in vivo validation; single lab","pmids":["24740500"],"is_preprint":false},{"year":2023,"finding":"In activated microglia, NR4A1 localizes to cytoplasmic processing bodies (P-bodies) and functions as an RNA-binding protein that directly binds and destabilizes Tnf mRNA in an m6A-dependent manner, providing post-transcriptional regulation of TNF production.","method":"Conditional microglial Nr4a1 knockout, RNA-binding protein assays, m6A assays, P-body colocalization, ischemic stroke mouse model","journal":"PLOS Biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO, direct RNA binding demonstrated, m6A dependence shown, in vivo disease model; multiple orthogonal methods","pmids":["37486903"],"is_preprint":false},{"year":2003,"finding":"Nur77 is required for caspase-independent macrophage cell death downstream of TLR2/TLR4 signaling; ERK (downstream of TLR) and MEF2 transcription factor activity (upregulated by caspase inhibition) are both required for Nur77 induction and macrophage death.","method":"Nr4a1-/- macrophages, TLR2/4 signaling inhibitors, reporter gene analysis of Nur77 promoter, septic mouse model","journal":"Journal of Experimental Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with promoter analysis and in vivo model; single lab","pmids":["12782711"],"is_preprint":false},{"year":2011,"finding":"TR3 transcriptionally regulates Nanog in gastric cancer stem cells; TR3 knockdown decreases Nanog and Oct-4 expression and suppresses stem-like properties including tumorsphere formation.","method":"siRNA knockdown, promoter reporter assays, tumorsphere assays, gene expression analysis","journal":"Cancer Letters","confidence":"Low","confidence_rationale":"Tier 3 — reporter assays and knockdown but mechanistic detail limited; single lab","pmids":["23043761"],"is_preprint":false},{"year":2003,"finding":"TR3 induces E2F1 expression by binding to a TR3 response element (TR3RE) in the E2F1 promoter (−316 to −324 bp) with a Kd of 6.29 nM; this transcriptional activation is required for TR3-mediated apoptosis in LNCaP prostate cancer cells.","method":"Promoter reporter assays, EMSA with Kd determination, dominant-negative TR3, antisense E2F1","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 — EMSA with quantitative binding, promoter mutagenesis, and functional epistasis; single lab","pmids":["12947120"],"is_preprint":false},{"year":2011,"finding":"TR3/Nur77 participates in cisplatin-induced apoptosis through Chk2 kinase-mediated phosphorylation of TR3; phosphorylated TR3 binds to response elements on BRE and RNF-7 promoters, negatively regulating these anti-apoptotic genes.","method":"Co-immunoprecipitation, kinase assays, ChIP, apoptosis assays, Apc(min/+)/TR3-/- mouse models","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical Chk2-TR3 interaction, ChIP, and in vivo genetic validation; single lab","pmids":["22159226"],"is_preprint":false},{"year":2023,"finding":"Mst1 kinase phosphorylates Nur77 at threonine 366 (identified by in vitro kinase assay and LC-MS/MS), which increases Nur77 transcriptional activity and upregulates downstream target β3-integrin, promoting trophoblast-uterine epithelium adhesion and embryo implantation.","method":"In vitro kinase assay, LC-MS/MS phosphosite identification, phos-tag SDS-PAGE, specific phospho-antibody, reporter assays, mouse implantation model","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay with LC-MS/MS site identification, phospho-specific antibody validation, functional in vivo rescue; multiple orthogonal methods","pmids":["36623453"],"is_preprint":false},{"year":2015,"finding":"Nur77 increases thrombomodulin mRNA stability in vascular endothelial cells (without affecting promoter activity), while Nor1 increases thrombomodulin expression through induction of KLF2 and KLF4; Nur77 deficiency increases susceptibility to arterial thrombosis.","method":"Adenovirus-mediated overexpression, Nur77-/- mice, mRNA stability assays, reporter assays, thrombosis models","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"Medium","confidence_rationale":"Tier 2 — mRNA stability assays plus in vivo KO thrombosis model; single lab","pmids":["26634653"],"is_preprint":false},{"year":2024,"finding":"NR4A1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in cardiomyocytes; semaglutide reduces NR4A1 expression and its translocation to mitochondria through the Creb5/NR4A1 axis in the PI3K/AKT pathway.","method":"NR4A1 knockdown, metabolomics, transcriptional analysis, confocal imaging, mouse heart failure model","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 — NR4A1 knockdown with metabolomics and in vivo model; single lab","pmids":["38834564"],"is_preprint":false}],"current_model":"NR4A1 (Nur77/TR3) is a ligand-independent orphan nuclear receptor that functions as a transcription factor in the nucleus (activating or repressing target genes including E2F1, CYP11B2, Nanog, Cebpa, and Wnt target genes) and, upon specific apoptotic stimuli, translocates to mitochondria or the ER where it binds Bcl-2 and induces a conformational change converting it from a pro-survival to a pro-apoptotic protein; its dual nuclear/cytoplasmic activities are controlled by post-translational modifications (phosphorylation by Akt at Ser-350, JNK at Ser-95, Chk2, pp90rsk, ERK2, Mst1 at Thr-366, and p38α; SUMOylation by PIAS3/SUMO2-3 followed by RNF4-mediated ubiquitination and degradation) and by protein interactions (with Bcl-2, p65/NF-κB, p53, FHL2, PRMT1, Pin1, LKB1, and RXRα) that collectively determine cell fate (proliferation, apoptosis, autophagy/mitophagy) in a context- and localization-dependent manner."},"narrative":{"teleology":[{"year":1993,"claim":"Mapping the functional architecture of Nur77 established that its transactivation resides in the N-terminal domain, that the C-terminal domain regulates this activity, and that phosphorylation by pp90rsk at Ser-354 modifies the protein, providing the first molecular framework for understanding how signal-dependent phosphorylation tunes an orphan receptor.","evidence":"Deletion mapping, in vitro kinase assays, and in vivo radiolabeling in transfected cells","pmids":["8232315"],"confidence":"High","gaps":["Physiological kinase hierarchy upstream of pp90rsk-Nur77 not defined","No structural data on how phosphorylation alters DNA binding"]},{"year":1994,"claim":"Dominant-negative Nur77 blocked TCR-induced apoptosis in T-cell hybridomas, establishing Nur77 as a necessary mediator of activation-induced cell death and positioning it as a central effector in thymic negative selection.","evidence":"Dominant-negative overexpression and EMSA in T-cell hybridomas","pmids":["8121493"],"confidence":"High","gaps":["Downstream effector mechanism unknown at this stage","Redundancy with other NR4A family members not addressed"]},{"year":1996,"claim":"Genetic epistasis in transgenic mice showed Nur77-driven thymocyte apoptosis required Fas ligand, linking a nuclear receptor to the extrinsic death pathway and resolving a key downstream effector question.","evidence":"Nur77 transgenic crossed to gld/gld (FasL-mutant) mice; flow cytometry","pmids":["8643610"],"confidence":"High","gaps":["Whether FasL is a direct transcriptional target of Nur77 not shown","Pathway may differ in peripheral T cells"]},{"year":1997,"claim":"The glucocorticoid receptor was shown to antagonize Nur77-dependent transactivation at the POMC NurRE without requiring GR DNA binding, revealing crosstalk between steroid and orphan receptor signaling on a physiological promoter.","evidence":"Reporter assays, in vitro binding, GR mutant analysis in endocrine and lymphoid cells","pmids":["9315653"],"confidence":"High","gaps":["Whether GR-Nur77 antagonism operates genome-wide or is promoter-selective","In vivo significance in HPA axis not tested"]},{"year":2001,"claim":"Akt was identified as a kinase that phosphorylates Nur77 at Ser-350 in the DNA-binding domain, reducing transcriptional activity by up to 85%, revealing a direct mechanism by which PI3K/Akt survival signaling neutralizes Nur77 function.","evidence":"In vitro kinase assay, in vivo phosphorylation, site-directed mutagenesis, reporter assays","pmids":["11274386"],"confidence":"High","gaps":["Whether Akt phosphorylation also influences Nur77 subcellular localization not tested here","Relative contribution of Ser-350 vs. other sites unclear"]},{"year":2003,"claim":"Several studies collectively established that Nur77 subcellular localization dictates its biological output: nuclear Nur77 drives proliferation via DNA binding and transactivation (e.g., E2F1 induction with Kd ~6 nM), while cytoplasmic/mitochondrial Nur77 triggers apoptosis through BAX recruitment and cytochrome c release, with JNK-mediated phosphorylation switching Nur77 from a nuclear mitogen to an apoptosis inducer.","evidence":"Confocal imaging, siRNA, GFP-Nur77 mutants, EMSA on E2F1 promoter, JNK kinase assays, colon cancer and prostate cancer cell systems","pmids":["14612408","14500374","12947120"],"confidence":"High","gaps":["Nuclear export mechanism not molecularly defined","Relative contribution of BAX versus Bcl-2 pathways in different tissues unresolved"]},{"year":2004,"claim":"The direct Nur77–Bcl-2 interaction was mapped to the N-terminal loop of Bcl-2, demonstrating that Nur77 induces a conformational change exposing the Bcl-2 BH3 domain and converting Bcl-2 from anti- to pro-apoptotic—a landmark mechanism linking an orphan receptor to intrinsic apoptosis at mitochondria.","evidence":"Reciprocal Co-IP, domain mutagenesis, mitochondrial fractionation, cytochrome c release assays in multiple cell types","pmids":["14980220"],"confidence":"High","gaps":["No structural model of the Nur77–Bcl-2 complex","Signals specifying Nur77 mitochondrial targeting remain unclear"]},{"year":2006,"claim":"Multiple discoveries in 2006 expanded the regulatory network: JNK phosphorylation at Ser-95 was shown to trigger Nur77 ubiquitination and degradation, Nur77 was found to drive angiogenesis through transcriptional activity in endothelial cells, and Nur77 was shown to translocate to the ER to engage Bcl-2 and trigger ER-stress-associated apoptosis via caspase-4.","evidence":"In vitro kinase assays with Ser95 mutagenesis; HUVEC assays with dominant-negative mutants and Nur77−/− mice; ER fractionation and Ca²⁺/caspase assays","pmids":["17023523","16520388","17543302"],"confidence":"High","gaps":["ER translocation signal on Nur77 not identified","Whether ER and mitochondrial Bcl-2 engagement are simultaneous or sequential unknown"]},{"year":2007,"claim":"Nur77 was shown to heterodimerize with RXRα, block p300-mediated RXRα acetylation, and—upon 9-cis retinoic acid stimulation—co-translocate with RXRα from the nucleus to mitochondria to induce apoptosis, integrating retinoid signaling with Nur77 mitochondrial function.","evidence":"Co-IP, acetylation assays, subcellular fractionation, confocal microscopy","pmids":["17761950"],"confidence":"Medium","gaps":["Single lab; independent replication pending","RXRα–Nur77 stoichiometry and dynamics at mitochondria unknown"]},{"year":2008,"claim":"Two discoveries clarified protein-level regulation: Akt phosphorylation of cytoplasmic Nur77 was shown to block mitochondrial targeting (resolving the gap from 2001), and PRMT1 was found to stabilize Nur77 protein and enhance its DNA binding in a methyltransferase-independent manner while Nur77 reciprocally inhibited PRMT1 catalytic activity.","evidence":"Co-IP, kinase assays, confocal imaging, PRMT1 methyltransferase assays, Nur77−/− mice","pmids":["18713840","19095693"],"confidence":"High","gaps":["In vivo significance of PRMT1–Nur77 reciprocal regulation not fully tested","How Akt access to cytoplasmic Nur77 is spatially regulated unclear"]},{"year":2011,"claim":"A burst of studies in 2011 defined NR4A1's roles across multiple tissues: it is cell-intrinsically required for Ly6C− patrolling monocyte survival; it suppresses NF-κB in macrophages; it disrupts β-catenin/TCF4 on Wnt target promoters (antagonized by GSK3β phosphorylation); FHL2 represses Nur77 DNA binding; Pin1 isomerizes phospho-Nur77 to stabilize it and promote cyclin D2 transactivation; it modulates endothelial permeability through eNOS and junction proteins; and Chk2 phosphorylation of Nur77 enables repression of anti-apoptotic genes BRE and RNF-7.","evidence":"Nr4a1−/− and chimeric mice, ChIP, domain mutagenesis, yeast two-hybrid, Pin1 binding assays, kinase assays, vascular permeability models","pmids":["21725321","22194622","21873734","22049082","22002310","21730126","22159226"],"confidence":"High","gaps":["Relative importance of the many phosphorylation sites in integrating signals not systematically compared","Tissue-specific weighting of nuclear vs. cytoplasmic functions still unclear"]},{"year":2012,"claim":"Two studies revealed non-transcriptional signaling roles: Nur77 sequesters LKB1 in the nucleus to attenuate AMPK activation (reversed by the small molecule TMPA), and Nur77 forms a trimeric complex with TSC1/TSC2 that promotes TSC2 proteasomal degradation to activate mTORC1, driving cardiac hypertrophy.","evidence":"Co-IP, subcellular fractionation, AMPK assays, compound binding, Nr4a1−/− mice; trimeric complex Co-IP, proteasome inhibition, cardiac hypertrophy models","pmids":["22983157","23197407"],"confidence":"High","gaps":["Whether LKB1 sequestration and TSC2 degradation are coordinated or context-exclusive unknown","Structural basis of trimeric TSC complex assembly not determined"]},{"year":2015,"claim":"NR4A1's anti-inflammatory mechanism was directly demonstrated: it physically blocks p65 binding to κB elements, and LPS-activated p38α phosphorylation of Nur77 relieves this block; separately, Nr4a1 suppresses Runx3 transcription in CD8+ T cells by recruiting CoREST, modulating T cell differentiation.","evidence":"Co-IP, ChIP, phosphorylation assays, sepsis model; Nr4a1−/− mice, ChIP for CoREST, flow cytometry","pmids":["25822914","25762306"],"confidence":"High","gaps":["Whether p38α phosphosite on Nur77 overlaps with other kinase sites","CoREST recruitment mechanism to Runx3 not structurally resolved"]},{"year":2017,"claim":"The SUMO-ubiquitin degradation axis for NR4A1 was defined: PIAS3-mediated SUMO2/3 conjugation at two sites targets NR4A1 for RNF4-dependent polyubiquitination and proteasomal degradation, with SENP1 opposing this modification, providing a unified mechanism for post-translational Nur77 turnover that affects NF-κB signaling output.","evidence":"SUMOylation and ubiquitination assays, site-directed mutagenesis, PIAS3/SENP1 manipulation, NF-κB reporters","pmids":["28622293"],"confidence":"High","gaps":["How SUMO-dependent degradation is coordinated with JNK/Ser95-dependent ubiquitination","In vivo validation of SUMO-site mutants not performed"]},{"year":2018,"claim":"NR4A1 was established as a metabolic regulator in macrophages (downregulating IDH to limit succinate accumulation and inflammatory output) and in hematopoietic stem cells (activating Cebpa via a hematopoietic-specific enhancer and antagonizing NF-κB to maintain quiescence).","evidence":"Nr4a1−/− macrophages with metabolomics and SDH epistasis; conditional NR4A1/NR4A3 double-KO with ChIP and gene profiling","pmids":["30134173","29343483"],"confidence":"High","gaps":["Whether IDH regulation is direct transcriptional or indirect","NR4A1 versus NR4A3 individual contributions to HSC maintenance not fully separated"]},{"year":2021,"claim":"Ubiquitinated mitochondrial Nur77 was shown to undergo liquid-liquid phase separation, forming condensates through multivalent interactions between its N-terminal IDR and p62/SQSTM1 PB1 domain, coordinating mitophagy of damaged mitochondria—a fundamentally new biophysical mechanism for this receptor.","evidence":"In vitro phase separation reconstitution, domain mutagenesis, live-cell imaging, mitophagy flux assays","pmids":["34645818"],"confidence":"High","gaps":["Whether phase separation occurs in vivo under physiological (non-overexpression) conditions","Ubiquitin chain type specificity for condensate formation not defined"]},{"year":2023,"claim":"Two studies revealed unexpected non-nuclear functions: NR4A1 localizes to P-bodies in activated microglia where it directly binds and destabilizes Tnf mRNA in an m6A-dependent manner, and Mst1 kinase phosphorylates Nur77 at Thr-366 to enhance transcriptional activity and promote embryo implantation via β3-integrin.","evidence":"Conditional microglial Nr4a1 KO, RNA-binding assays, m6A analysis, P-body colocalization; in vitro kinase/LC-MS/MS, phospho-specific antibody, mouse implantation model","pmids":["37486903","36623453"],"confidence":"High","gaps":["Scope of NR4A1 RNA-binding targets beyond Tnf unknown","Whether m6A-dependent RNA decay is a general NR4A1 function outside microglia not tested"]},{"year":null,"claim":"Major unresolved questions include the structural basis of the Nur77–Bcl-2 and Nur77–p62 interactions, the hierarchy and crosstalk among the >8 documented phosphorylation events, the full spectrum of NR4A1 RNA targets, and how tissue-specific contexts select between its nuclear transcriptional, cytoplasmic signaling, mitochondrial apoptotic, and P-body RNA-regulatory functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of any NR4A1 complex","Integrated phospho-signaling code not determined","RNA targetome outside Tnf unknown","Redundancy with NR4A2/NR4A3 incompletely resolved in most tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,4,12,17,22,28,29,30,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,4,28,36]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6,15,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,4,5,6,12,17,22,28,29,30,36]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,10,11,16,40]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11,16,33]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,7,13,16,36,37]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7,8,9,29,30,31,32,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,6,11,14,17,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,4,12,22,28,29,30,36]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,9,40]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[33]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[19,25]}],"complexes":[],"partners":["BCL2","RELA","TP53","SQSTM1","FHL2","PRMT1","PIN1","STK11"],"other_free_text":[]},"mechanistic_narrative":"NR4A1 (Nur77/TR3) is an immediate-early orphan nuclear receptor that integrates transcriptional, cytoplasmic, and organelle-targeted activities to govern cell fate decisions—apoptosis, proliferation, inflammation, and metabolic reprogramming—across lymphoid, myeloid, endothelial, and epithelial lineages. In the nucleus, NR4A1 acts as a sequence-specific transcription factor that activates targets such as CYP11B2, E2F1, Cebpa, and eNOS, while repressing NF-κB-dependent inflammatory genes through direct interaction with p65 and recruiting co-repressors such as CoREST to loci including Runx3 [PMID:14645496, PMID:25822914, PMID:29343483, PMID:25762306]. Upon apoptotic stimuli, NR4A1 translocates to mitochondria where it binds the N-terminal loop of Bcl-2 and induces a conformational change that exposes the BH3 domain, converting Bcl-2 from a pro-survival to a pro-apoptotic protein; ubiquitinated mitochondrial NR4A1 further drives mitophagy by forming p62-dependent liquid-liquid phase-separated condensates [PMID:14980220, PMID:34645818]. NR4A1 activity is tuned by multiple post-translational modifications—Akt phosphorylation at Ser-350 suppresses DNA binding and blocks mitochondrial targeting, JNK phosphorylation at Ser-95 triggers its degradation, and SUMO2/3 conjugation by PIAS3 followed by RNF4-mediated polyubiquitination controls its protein turnover—while interactions with LKB1, RXRα, Pin1, PRMT1, and FHL2 modulate its transcriptional output and subcellular routing [PMID:11274386, PMID:18713840, PMID:17023523, PMID:28622293, PMID:22983157, PMID:22002310]."},"prefetch_data":{"uniprot":{"accession":"P22736","full_name":"Nuclear receptor subfamily 4immunitygroup A member 1","aliases":["Early response protein NAK1","Nuclear hormone receptor NUR/77","Nur77","Orphan nuclear receptor HMR","Orphan nuclear receptor TR3","ST-59","Testicular receptor 3"],"length_aa":598,"mass_kda":64.5,"function":"Orphan nuclear receptor. Binds the NGFI-B response element (NBRE) 5'-AAAGGTCA-3' (PubMed:18690216, PubMed:8121493, PubMed:9315652). Binds 9-cis-retinoic acid outside of its ligand-binding (NR LBD) domain (PubMed:18690216). Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation (PubMed:22983157). Regulates the inflammatory response in macrophages by regulating metabolic adaptations during inflammation, including repressing the transcription of genes involved in the citric acid cycle (TCA) (By similarity). Inhibits NF-kappa-B signaling by binding to low-affinity NF-kappa-B binding sites, such as at the IL2 promoter (PubMed:15466594). May act concomitantly with NR4A2 in regulating the expression of delayed-early genes during liver regeneration (By similarity). Plays a role in the vascular response to injury (By similarity) In the cytosol, upon its detection of both bacterial lipopolysaccharide (LPS) and NBRE-containing mitochondrial DNA released by GSDMD pores during pyroptosis, it promotes non-canonical NLRP3 inflammasome activation by stimulating association of NLRP3 and NEK7","subcellular_location":"Nucleus; Cytoplasm, cytosol; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P22736/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR4A1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR4A1","total_profiled":1310},"omim":[{"mim_id":"613890","title":"3-@BETA-HYDROXYSTEROID DEHYDROGENASE 2; HSD3B2","url":"https://www.omim.org/entry/613890"},{"mim_id":"613677","title":"HYPERALDOSTERONISM, FAMILIAL, TYPE III; HALD3","url":"https://www.omim.org/entry/613677"},{"mim_id":"609455","title":"PROLINE-, GLUTAMIC ACID-, AND LEUCINE-RICH PROTEIN 1; PELP1","url":"https://www.omim.org/entry/609455"},{"mim_id":"608070","title":"HOMOCYSTEINE- AND ENDOPLASMIC RETICULUM STRESS-INDUCIBLE PROTEIN, UBIQUITIN-LIKE DOMAIN-CONTAINING, 1; HERPUD1","url":"https://www.omim.org/entry/608070"},{"mim_id":"606542","title":"HISTONE DEACETYLASE 7A; HDAC7A","url":"https://www.omim.org/entry/606542"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NR4A1"},"hgnc":{"alias_symbol":["TR3","N10","NAK-1","NGFIB","NUR77"],"prev_symbol":["HMR","GFRP1"]},"alphafold":{"accession":"P22736","domains":[{"cath_id":"3.30.50.10","chopping":"275-329","consensus_level":"high","plddt":96.4367,"start":275,"end":329},{"cath_id":"1.10.565.10","chopping":"360-594","consensus_level":"high","plddt":90.1641,"start":360,"end":594}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22736","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22736-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22736-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR4A1","jax_strain_url":"https://www.jax.org/strain/search?query=NR4A1"},"sequence":{"accession":"P22736","fasta_url":"https://rest.uniprot.org/uniprotkb/P22736.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22736/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22736"}},"corpus_meta":[{"pmid":"14980220","id":"PMC_14980220","title":"Conversion 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in Bcl-2 that exposes its BH3 domain and converts Bcl-2 from an anti-apoptotic to a pro-apoptotic protein, triggering cytochrome c release and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, mitochondrial fractionation, confocal microscopy, functional apoptosis assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP, domain mutagenesis, multiple orthogonal functional assays; highly cited foundational study\",\n      \"pmids\": [\"14980220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Nur77 is required for activation-induced apoptosis in T-cell hybridomas; a dominant-negative Nur77 blocks TCR-induced cell death, establishing Nur77 as a necessary mediator of this pathway.\",\n      \"method\": \"Dominant-negative overexpression, gel shift analysis (EMSA), subtractive hybridization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative epistasis with defined phenotypic readout; highly cited foundational study replicated in subsequent work\",\n      \"pmids\": [\"8121493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Akt physically interacts with Nur77 and phosphorylates it at Ser-350 within its DNA-binding domain in a PI3K-dependent manner, reducing Nur77 transcriptional activity by 50–85%.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, in vivo phosphorylation assay, luciferase reporter assay, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus in vivo validation and mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"11274386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Nur77 transactivation activity resides in its N-terminal domain; the C-terminal domain regulates this activity. Deletion of the domain immediately C-terminal to the zinc fingers abolishes DNA binding and nuclear localization. Nur77 is phosphorylated primarily at its N-terminal domain, and pp90rsk phosphorylates Ser-354 in vitro and in vivo.\",\n      \"method\": \"Deletion mapping, transactivation assays, in vitro phosphorylation with recombinant kinases, in vivo radiolabeling\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic deletion mapping plus in vitro and in vivo phosphorylation assays\",\n      \"pmids\": [\"8232315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TR3/Nur77 nuclear functions are controlled by subcellular localization: nuclear TR3 promotes cell proliferation via its DNA-binding and transactivation domains, while mitochondrial TR3 induces apoptosis independently of these domains. EGF/serum induces nuclear TR3 mitogenesis; MEKK1 activates JNK which phosphorylates TR3 and abolishes its DNA binding, blocking its mitogenic function.\",\n      \"method\": \"Confocal microscopy, siRNA knockdown, ectopic expression of TR3 mutants, BrdU incorporation, JNK kinase assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (live imaging, mutant analysis, siRNA, kinase assays) in a single study\",\n      \"pmids\": [\"14612408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. Compound TMPA binds Nur77 with high affinity, releasing LKB1 to the cytoplasm where it phosphorylates AMPKα.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, AMPK activity assays, compound binding assays, knockout mouse validation\",\n      \"journal\": \"Nature Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, fractionation, functional rescue, in vivo knockout confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"22983157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nur77 directly associates with the p65 subunit of NF-κB to block its binding to the κB element, suppressing inflammatory cytokine production. LPS-activated p38α phosphorylates Nur77, counteracting this NF-κB suppression.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assays, phosphorylation assays, compound screening\",\n      \"journal\": \"Nature Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, phosphorylation assays, and in vivo sepsis model; multiple orthogonal methods\",\n      \"pmids\": [\"25822914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Nur77/N10 transgenic thymocytes undergo apoptosis through upregulation of Fas ligand (FasL) expression; crossing to gld/gld mice (FasL-mutant) rescues the apoptosis phenotype, demonstrating Nur77-driven thymocyte apoptosis requires the Fas/FasL pathway.\",\n      \"method\": \"Transgenic mouse model, genetic epistasis with gld mutation, flow cytometry for thymocyte populations, FasL expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis in transgenic/mutant mice with defined cellular phenotype\",\n      \"pmids\": [\"8643610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NR4A1 controls the differentiation and survival of Ly6C- (patrolling) monocytes in a cell-intrinsic manner; Nr4a1-/- mice lack patrolling monocytes, and residual Ly6C- cells in knockout bone marrow are arrested in S phase and undergo apoptosis.\",\n      \"method\": \"Knockout mouse analysis, bone marrow transplantation (chimera), flow cytometry, cell cycle analysis\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout plus BM chimera demonstrating cell-intrinsic requirement; multiple functional readouts\",\n      \"pmids\": [\"21725321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nur77 acts as an upstream transcriptional regulator of metabolic reprogramming in macrophages by downregulating isocitrate dehydrogenase (IDH) expression; Nur77-deficient macrophages accumulate higher succinate levels and produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner.\",\n      \"method\": \"Nr4a1-/- macrophages, metabolomics, IDH/SDH functional assays, cytokine measurements, atherosclerosis in vivo model\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with metabolomics and mechanistic epistasis; multiple orthogonal readouts\",\n      \"pmids\": [\"30134173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ubiquitinated mitochondrial Nur77 forms membraneless condensates through liquid-liquid phase separation; multivalent interaction between Nur77's N-terminal IDR and the PB1 domain of p62/SQSTM1, and between Nur77's UBA-interacting region and p62's UBA domain, coordinates sequestration of damaged mitochondria for mitophagy.\",\n      \"method\": \"Phase separation assays, co-immunoprecipitation, domain mutagenesis, live-cell imaging, mitophagy flux assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution of condensates, domain dissection, and functional mitophagy assays with mutagenesis\",\n      \"pmids\": [\"34645818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Akt phosphorylates cytoplasmic Nur77 through physical interaction with its N-terminus, blocking Nur77 mitochondrial targeting and disrupting the Nur77–Bcl-2 interaction required for apoptosis induction.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, confocal microscopy, subcellular fractionation, insulin stimulation\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods showing Akt-Nur77 interaction, phosphorylation, and functional consequence on mitochondrial localization\",\n      \"pmids\": [\"18713840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Glucocorticoid receptor (GR) antagonizes Nur77-dependent transcription at the NurRE element of the POMC gene by a mechanism similar to GR/AP-1 antagonism; GR also partly blunts CRH induction of Nur77 mRNA; in vitro binding and mutation analysis show GR antagonism of Nur77 does not require direct DNA binding by GR.\",\n      \"method\": \"Transfection/reporter assays, in vitro binding experiments, GR mutation analysis, Northern blotting\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding, mutagenesis, reporter assays in both endocrine and lymphoid cell contexts\",\n      \"pmids\": [\"9315653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TR3/Nur77 translocates to the endoplasmic reticulum (ER) upon CD437 treatment, interacts with ER-associated Bcl-2, triggers early Ca²⁺ release from the ER, and induces apoptosis via ER-specific caspase-4 activation in parallel with mitochondrial stress and caspase-9 activation.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, co-immunoprecipitation, Ca²⁺ measurement, caspase activity assays\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods but single lab study\",\n      \"pmids\": [\"17543302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TR3/Nur77 regulates mTORC1 signaling in lung cancer cells: it suppresses p53 (via a p300/TR3/Sp1 complex on GC-rich promoters including survivin), and in p53 wild-type cells, siTR3 activates p53 which induces sestrin2, activating AMPKα and inhibiting mTORC1.\",\n      \"method\": \"RNA interference, Western blot, ChIP, luciferase reporter assays, xenograft tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi + ChIP + reporter assays with in vivo validation; single lab\",\n      \"pmids\": [\"22081070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TR3/Nur77 directly interacts with p53 (not MDM2), blocks p53 acetylation (reducing MDM2 transcription), and prevents MDM2-induced p53 ubiquitination, resulting in MDM2 ubiquitination and degradation; TR3 also enhances p53-mediated apoptosis by UV.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, luciferase reporter, ubiquitination assay, acetylation assay\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — GST pulldown, Co-IP, and multiple biochemical assays demonstrating mechanism; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17139261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In colon cancer cells, butyrate- and NSAID-induced apoptosis involves nucleus-to-cytoplasm translocation of TR3/Nur77, with cytoplasmic (not direct mitochondrial) localization triggering BAX recruitment to mitochondria and cytochrome c release.\",\n      \"method\": \"GFP-TR3 live-cell imaging, TR3 mutant constructs, cytochrome c release assays, BAX co-localization\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with functionally validated mutants; single lab\",\n      \"pmids\": [\"14500374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TR3/Nur77 disrupts the association of β-catenin and TCF4 on chromatin and facilitates recruitment of transcriptional co-repressors to Wnt target gene promoters, suppressing Wnt signaling. GSK3β phosphorylates TR3, attenuating its inhibitory activity toward Wnt signaling in clinical colorectal cancers.\",\n      \"method\": \"ChIP, co-immunoprecipitation, reporter assays, knockout/transgenic mouse models, kinase assays on clinical samples\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, Co-IP, kinase assays, in vivo Apc(min/+) mouse models; multiple orthogonal methods\",\n      \"pmids\": [\"21873734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TR3/Nur77 forms a trimeric complex with TSC1/TSC2 that specifically promotes TSC2 degradation via the ubiquitin/proteasome pathway, activating mTORC1 (but not mTORC2) and leading to increased protein synthesis and cardiac hypertrophy in response to angiotensin II.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibition, TR3 knockout/knockdown mouse models, mTORC1 activity assays\",\n      \"journal\": \"EMBO Molecular Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of trimeric complex, in vivo knockout models, mechanistic pathway dissection; single lab but multiple methods\",\n      \"pmids\": [\"23197407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR4A1 is SUMOylated by SUMO2/3 at two specific sites; poly-SUMO modification targets NR4A1 for polyubiquitination by the SUMO-dependent E3 ligase RNF4 and subsequent proteasomal degradation. PIAS3 promotes SUMOylation and RNF4-mediated ubiquitination, while SENP1 de-conjugates SUMO; mutation of SUMO sites stabilizes NR4A1 and affects its regulation of NF-κB signaling.\",\n      \"method\": \"SUMOylation assays, ubiquitination assays, site-directed mutagenesis, PIAS3/SENP1 overexpression/knockdown, functional NF-κB reporter assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical SUMOylation/ubiquitination assays, mutagenesis of modification sites, functional validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28622293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FHL2 physically interacts with Nur77 (identified by yeast two-hybrid and Co-IP); each of FHL2's four LIM domains binds Nur77, and both the N-terminal domain and DNA-binding domain of Nur77 are involved. FHL2 represses Nur77 transcriptional activity dose-dependently by inhibiting Nur77 binding to DNA, as shown by ChIP on the enolase3 promoter.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, domain mapping, ChIP, shRNA knockdown, reporter assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus Co-IP plus ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"22049082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TR3/Nur77 modulates vascular permeability by transcriptionally increasing endothelial nitric-oxide synthase expression and downregulating endothelial junction proteins; both effects require TR3 transcriptional activity (transactivation and DNA-binding domains).\",\n      \"method\": \"Nur77-/- mice, transgenic overexpression, dominant-negative TR3, in vivo vascular permeability assays, TR3 mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic models (KO, transgenic, dominant-negative) plus domain mutant studies; multiple orthogonal approaches\",\n      \"pmids\": [\"21730126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TR3/Nur77 angiogenic activity in endothelial cells (proliferation, survival, tube formation) operates through its transactivation and DNA-binding domains (transcriptional activity); overexpression promotes angiogenesis in vivo while antisense inhibits VEGF-A-induced angiogenesis.\",\n      \"method\": \"Antisense/overexpression in HUVECs, dominant-negative mutants, endothelial-selective retroviral targeting in vivo, Nur77-/- mice with tumor models\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — TR3 mutant domain dissection, in vivo Nur77-/- tumor model, multiple orthogonal approaches\",\n      \"pmids\": [\"16520388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PRMT1 physically interacts with TR3/Nur77 and stabilizes TR3 protein (delaying degradation), thereby enhancing TR3 DNA binding and transcriptional activity in a methyltransferase-independent manner. In turn, TR3 binding to the catalytic domain of PRMT1 inhibits PRMT1 methyltransferase activity, affecting STAT3 and Sam68 methylation.\",\n      \"method\": \"Co-immunoprecipitation, methyltransferase activity assays, protein stability assays, luciferase reporter assays, TR3 knockout mice with agonist\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, in vitro methyltransferase assays, and in vivo knockout validation; multiple orthogonal methods\",\n      \"pmids\": [\"19095693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pin1 binds phospho-Ser/Thr-Pro motifs on TR3 (at least three sites; key site Ser95-Pro), isomerizes them, stabilizes TR3 by retarding degradation, and enhances TR3 transactivation through phospho-Ser431 isomerization by ERK2. Pin1 also promotes TR3 targeting to the cyclin D2 promoter and recruitment of p300.\",\n      \"method\": \"Co-immunoprecipitation, in vitro Pin1 binding assays, protein stability assays, ChIP, proliferation/tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical Pin1-substrate assays, stability analysis, ChIP; in vivo validation; multiple methods\",\n      \"pmids\": [\"22002310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"JNK phosphorylates TR3 specifically at Ser95 (mediated through MKK4/MKK7 → JNK1), inducing TR3 ubiquitination and degradation, abolishing its mitogenic activity, and blocking TR3 DNA binding and transactivation.\",\n      \"method\": \"In vitro kinase assays, site-directed mutagenesis (Ser95), ubiquitination assays, reporter assays, co-immunoprecipitation\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay with mutagenesis plus functional assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17023523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TR3/Nur77 interacts with RXRα and blocks p300-induced acetylation of RXRα at Lys145 by sequestering RXRα from p300. 9-cis retinoic acid enhances TR3-RXRα association and promotes co-translocation from nucleus to mitochondria, inducing apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assays, luciferase reporter, subcellular fractionation, confocal microscopy\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, biochemical acetylation assay, live-cell imaging; single lab\",\n      \"pmids\": [\"17761950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PML physically interacts with the DNA-binding domain of Nur77 (amino acids 267–332; coiled-coil domain of PML) in vitro and in vivo, and represses Nur77 transcription by interfering with Nur77 DNA binding in a dose-dependent manner.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, EMSA, colocalization by confocal microscopy, domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GST pulldown, Co-IP, and EMSA confirming mechanism; single lab\",\n      \"pmids\": [\"12032831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NGFI-B/NR4A1 binds to two functional NBRE elements in the CYP11B2 (aldosterone synthase) promoter and transactivates CYP11B2 expression in adrenocortical cells; angiotensin II strongly induces NGFI-B and NURR1 protein, and calmodulin kinase partially mediates this induction.\",\n      \"method\": \"Transient transfection/reporter assays, EMSAs, promoter deletion/mutagenesis, Western blotting, kinase inhibition\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — EMSA, promoter mutagenesis, and reporter assays; multiple orthogonal methods\",\n      \"pmids\": [\"14645496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nr4a1 directly suppresses Runx3 transcription in CD8+ T cells by recruiting the co-repressor CoREST to the Runx3 gene; loss of Nr4a1 increases Runx3 expression and causes a 2-fold increase in CD8+ T cell frequency.\",\n      \"method\": \"Nr4a1 knockout mice, ChIP (CoREST recruitment), RNA interference, flow cytometry\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct binding and co-repressor recruitment; KO mouse phenotype; single lab\",\n      \"pmids\": [\"25762306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 and NR4A3 directly bind a hematopoietic-specific Cebpa enhancer to activate Cebpa transcription, restricting HSC proliferation; they also occupy regulatory regions of NF-κB-regulated inflammatory cytokines to antagonize NF-κB signaling and maintain HSC quiescence.\",\n      \"method\": \"Conditional double-knockout mice, ChIP, gene expression profiling, NF-κB signaling assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO plus ChIP with molecular profiling; multiple orthogonal methods\",\n      \"pmids\": [\"29343483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NR4A1 deletion in macrophages enhances TLR4 signaling and increases phosphorylation of the p65 subunit of NF-κB, polarizing macrophages to a pro-inflammatory M1 phenotype; NF-κB inhibition blocks the excess activation of Nur77-/- macrophages.\",\n      \"method\": \"Nr4a1-/- chimeric mice, Western blot for p65 phosphorylation, NF-κB inhibitor experiments, cytokine measurement\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse with NF-κB epistasis; single lab\",\n      \"pmids\": [\"22194622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nr4a1 mediates the anti-inflammatory effects of apoptotic cell phagocytosis in macrophages; Nr4a1 deletion prevents inhibition of NF-κB signaling and IL-12 repression normally induced by apoptotic cells, demonstrating Nr4a1 is required for tolerance to dying-self signals.\",\n      \"method\": \"Nr4a1-/- macrophages, NF-κB reporter assay, IL-12 measurement, in vivo pristane-induced lupus model\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with NF-κB assays and in vivo validation; single lab\",\n      \"pmids\": [\"24740500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In activated microglia, NR4A1 localizes to cytoplasmic processing bodies (P-bodies) and functions as an RNA-binding protein that directly binds and destabilizes Tnf mRNA in an m6A-dependent manner, providing post-transcriptional regulation of TNF production.\",\n      \"method\": \"Conditional microglial Nr4a1 knockout, RNA-binding protein assays, m6A assays, P-body colocalization, ischemic stroke mouse model\",\n      \"journal\": \"PLOS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO, direct RNA binding demonstrated, m6A dependence shown, in vivo disease model; multiple orthogonal methods\",\n      \"pmids\": [\"37486903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nur77 is required for caspase-independent macrophage cell death downstream of TLR2/TLR4 signaling; ERK (downstream of TLR) and MEF2 transcription factor activity (upregulated by caspase inhibition) are both required for Nur77 induction and macrophage death.\",\n      \"method\": \"Nr4a1-/- macrophages, TLR2/4 signaling inhibitors, reporter gene analysis of Nur77 promoter, septic mouse model\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with promoter analysis and in vivo model; single lab\",\n      \"pmids\": [\"12782711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TR3 transcriptionally regulates Nanog in gastric cancer stem cells; TR3 knockdown decreases Nanog and Oct-4 expression and suppresses stem-like properties including tumorsphere formation.\",\n      \"method\": \"siRNA knockdown, promoter reporter assays, tumorsphere assays, gene expression analysis\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — reporter assays and knockdown but mechanistic detail limited; single lab\",\n      \"pmids\": [\"23043761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TR3 induces E2F1 expression by binding to a TR3 response element (TR3RE) in the E2F1 promoter (−316 to −324 bp) with a Kd of 6.29 nM; this transcriptional activation is required for TR3-mediated apoptosis in LNCaP prostate cancer cells.\",\n      \"method\": \"Promoter reporter assays, EMSA with Kd determination, dominant-negative TR3, antisense E2F1\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — EMSA with quantitative binding, promoter mutagenesis, and functional epistasis; single lab\",\n      \"pmids\": [\"12947120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TR3/Nur77 participates in cisplatin-induced apoptosis through Chk2 kinase-mediated phosphorylation of TR3; phosphorylated TR3 binds to response elements on BRE and RNF-7 promoters, negatively regulating these anti-apoptotic genes.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, ChIP, apoptosis assays, Apc(min/+)/TR3-/- mouse models\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical Chk2-TR3 interaction, ChIP, and in vivo genetic validation; single lab\",\n      \"pmids\": [\"22159226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mst1 kinase phosphorylates Nur77 at threonine 366 (identified by in vitro kinase assay and LC-MS/MS), which increases Nur77 transcriptional activity and upregulates downstream target β3-integrin, promoting trophoblast-uterine epithelium adhesion and embryo implantation.\",\n      \"method\": \"In vitro kinase assay, LC-MS/MS phosphosite identification, phos-tag SDS-PAGE, specific phospho-antibody, reporter assays, mouse implantation model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay with LC-MS/MS site identification, phospho-specific antibody validation, functional in vivo rescue; multiple orthogonal methods\",\n      \"pmids\": [\"36623453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nur77 increases thrombomodulin mRNA stability in vascular endothelial cells (without affecting promoter activity), while Nor1 increases thrombomodulin expression through induction of KLF2 and KLF4; Nur77 deficiency increases susceptibility to arterial thrombosis.\",\n      \"method\": \"Adenovirus-mediated overexpression, Nur77-/- mice, mRNA stability assays, reporter assays, thrombosis models\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mRNA stability assays plus in vivo KO thrombosis model; single lab\",\n      \"pmids\": [\"26634653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR4A1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in cardiomyocytes; semaglutide reduces NR4A1 expression and its translocation to mitochondria through the Creb5/NR4A1 axis in the PI3K/AKT pathway.\",\n      \"method\": \"NR4A1 knockdown, metabolomics, transcriptional analysis, confocal imaging, mouse heart failure model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — NR4A1 knockdown with metabolomics and in vivo model; single lab\",\n      \"pmids\": [\"38834564\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR4A1 (Nur77/TR3) is a ligand-independent orphan nuclear receptor that functions as a transcription factor in the nucleus (activating or repressing target genes including E2F1, CYP11B2, Nanog, Cebpa, and Wnt target genes) and, upon specific apoptotic stimuli, translocates to mitochondria or the ER where it binds Bcl-2 and induces a conformational change converting it from a pro-survival to a pro-apoptotic protein; its dual nuclear/cytoplasmic activities are controlled by post-translational modifications (phosphorylation by Akt at Ser-350, JNK at Ser-95, Chk2, pp90rsk, ERK2, Mst1 at Thr-366, and p38α; SUMOylation by PIAS3/SUMO2-3 followed by RNF4-mediated ubiquitination and degradation) and by protein interactions (with Bcl-2, p65/NF-κB, p53, FHL2, PRMT1, Pin1, LKB1, and RXRα) that collectively determine cell fate (proliferation, apoptosis, autophagy/mitophagy) in a context- and localization-dependent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NR4A1 (Nur77/TR3) is an immediate-early orphan nuclear receptor that integrates transcriptional, cytoplasmic, and organelle-targeted activities to govern cell fate decisions—apoptosis, proliferation, inflammation, and metabolic reprogramming—across lymphoid, myeloid, endothelial, and epithelial lineages. In the nucleus, NR4A1 acts as a sequence-specific transcription factor that activates targets such as CYP11B2, E2F1, Cebpa, and eNOS, while repressing NF-κB-dependent inflammatory genes through direct interaction with p65 and recruiting co-repressors such as CoREST to loci including Runx3 [PMID:14645496, PMID:25822914, PMID:29343483, PMID:25762306]. Upon apoptotic stimuli, NR4A1 translocates to mitochondria where it binds the N-terminal loop of Bcl-2 and induces a conformational change that exposes the BH3 domain, converting Bcl-2 from a pro-survival to a pro-apoptotic protein; ubiquitinated mitochondrial NR4A1 further drives mitophagy by forming p62-dependent liquid-liquid phase-separated condensates [PMID:14980220, PMID:34645818]. NR4A1 activity is tuned by multiple post-translational modifications—Akt phosphorylation at Ser-350 suppresses DNA binding and blocks mitochondrial targeting, JNK phosphorylation at Ser-95 triggers its degradation, and SUMO2/3 conjugation by PIAS3 followed by RNF4-mediated polyubiquitination controls its protein turnover—while interactions with LKB1, RXRα, Pin1, PRMT1, and FHL2 modulate its transcriptional output and subcellular routing [PMID:11274386, PMID:18713840, PMID:17023523, PMID:28622293, PMID:22983157, PMID:22002310].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Mapping the functional architecture of Nur77 established that its transactivation resides in the N-terminal domain, that the C-terminal domain regulates this activity, and that phosphorylation by pp90rsk at Ser-354 modifies the protein, providing the first molecular framework for understanding how signal-dependent phosphorylation tunes an orphan receptor.\",\n      \"evidence\": \"Deletion mapping, in vitro kinase assays, and in vivo radiolabeling in transfected cells\",\n      \"pmids\": [\"8232315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological kinase hierarchy upstream of pp90rsk-Nur77 not defined\", \"No structural data on how phosphorylation alters DNA binding\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Dominant-negative Nur77 blocked TCR-induced apoptosis in T-cell hybridomas, establishing Nur77 as a necessary mediator of activation-induced cell death and positioning it as a central effector in thymic negative selection.\",\n      \"evidence\": \"Dominant-negative overexpression and EMSA in T-cell hybridomas\",\n      \"pmids\": [\"8121493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector mechanism unknown at this stage\", \"Redundancy with other NR4A family members not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Genetic epistasis in transgenic mice showed Nur77-driven thymocyte apoptosis required Fas ligand, linking a nuclear receptor to the extrinsic death pathway and resolving a key downstream effector question.\",\n      \"evidence\": \"Nur77 transgenic crossed to gld/gld (FasL-mutant) mice; flow cytometry\",\n      \"pmids\": [\"8643610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FasL is a direct transcriptional target of Nur77 not shown\", \"Pathway may differ in peripheral T cells\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The glucocorticoid receptor was shown to antagonize Nur77-dependent transactivation at the POMC NurRE without requiring GR DNA binding, revealing crosstalk between steroid and orphan receptor signaling on a physiological promoter.\",\n      \"evidence\": \"Reporter assays, in vitro binding, GR mutant analysis in endocrine and lymphoid cells\",\n      \"pmids\": [\"9315653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GR-Nur77 antagonism operates genome-wide or is promoter-selective\", \"In vivo significance in HPA axis not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Akt was identified as a kinase that phosphorylates Nur77 at Ser-350 in the DNA-binding domain, reducing transcriptional activity by up to 85%, revealing a direct mechanism by which PI3K/Akt survival signaling neutralizes Nur77 function.\",\n      \"evidence\": \"In vitro kinase assay, in vivo phosphorylation, site-directed mutagenesis, reporter assays\",\n      \"pmids\": [\"11274386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Akt phosphorylation also influences Nur77 subcellular localization not tested here\", \"Relative contribution of Ser-350 vs. other sites unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Several studies collectively established that Nur77 subcellular localization dictates its biological output: nuclear Nur77 drives proliferation via DNA binding and transactivation (e.g., E2F1 induction with Kd ~6 nM), while cytoplasmic/mitochondrial Nur77 triggers apoptosis through BAX recruitment and cytochrome c release, with JNK-mediated phosphorylation switching Nur77 from a nuclear mitogen to an apoptosis inducer.\",\n      \"evidence\": \"Confocal imaging, siRNA, GFP-Nur77 mutants, EMSA on E2F1 promoter, JNK kinase assays, colon cancer and prostate cancer cell systems\",\n      \"pmids\": [\"14612408\", \"14500374\", \"12947120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear export mechanism not molecularly defined\", \"Relative contribution of BAX versus Bcl-2 pathways in different tissues unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The direct Nur77–Bcl-2 interaction was mapped to the N-terminal loop of Bcl-2, demonstrating that Nur77 induces a conformational change exposing the Bcl-2 BH3 domain and converting Bcl-2 from anti- to pro-apoptotic—a landmark mechanism linking an orphan receptor to intrinsic apoptosis at mitochondria.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mutagenesis, mitochondrial fractionation, cytochrome c release assays in multiple cell types\",\n      \"pmids\": [\"14980220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the Nur77–Bcl-2 complex\", \"Signals specifying Nur77 mitochondrial targeting remain unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Multiple discoveries in 2006 expanded the regulatory network: JNK phosphorylation at Ser-95 was shown to trigger Nur77 ubiquitination and degradation, Nur77 was found to drive angiogenesis through transcriptional activity in endothelial cells, and Nur77 was shown to translocate to the ER to engage Bcl-2 and trigger ER-stress-associated apoptosis via caspase-4.\",\n      \"evidence\": \"In vitro kinase assays with Ser95 mutagenesis; HUVEC assays with dominant-negative mutants and Nur77−/− mice; ER fractionation and Ca²⁺/caspase assays\",\n      \"pmids\": [\"17023523\", \"16520388\", \"17543302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER translocation signal on Nur77 not identified\", \"Whether ER and mitochondrial Bcl-2 engagement are simultaneous or sequential unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Nur77 was shown to heterodimerize with RXRα, block p300-mediated RXRα acetylation, and—upon 9-cis retinoic acid stimulation—co-translocate with RXRα from the nucleus to mitochondria to induce apoptosis, integrating retinoid signaling with Nur77 mitochondrial function.\",\n      \"evidence\": \"Co-IP, acetylation assays, subcellular fractionation, confocal microscopy\",\n      \"pmids\": [\"17761950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; independent replication pending\", \"RXRα–Nur77 stoichiometry and dynamics at mitochondria unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two discoveries clarified protein-level regulation: Akt phosphorylation of cytoplasmic Nur77 was shown to block mitochondrial targeting (resolving the gap from 2001), and PRMT1 was found to stabilize Nur77 protein and enhance its DNA binding in a methyltransferase-independent manner while Nur77 reciprocally inhibited PRMT1 catalytic activity.\",\n      \"evidence\": \"Co-IP, kinase assays, confocal imaging, PRMT1 methyltransferase assays, Nur77−/− mice\",\n      \"pmids\": [\"18713840\", \"19095693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of PRMT1–Nur77 reciprocal regulation not fully tested\", \"How Akt access to cytoplasmic Nur77 is spatially regulated unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A burst of studies in 2011 defined NR4A1's roles across multiple tissues: it is cell-intrinsically required for Ly6C− patrolling monocyte survival; it suppresses NF-κB in macrophages; it disrupts β-catenin/TCF4 on Wnt target promoters (antagonized by GSK3β phosphorylation); FHL2 represses Nur77 DNA binding; Pin1 isomerizes phospho-Nur77 to stabilize it and promote cyclin D2 transactivation; it modulates endothelial permeability through eNOS and junction proteins; and Chk2 phosphorylation of Nur77 enables repression of anti-apoptotic genes BRE and RNF-7.\",\n      \"evidence\": \"Nr4a1−/− and chimeric mice, ChIP, domain mutagenesis, yeast two-hybrid, Pin1 binding assays, kinase assays, vascular permeability models\",\n      \"pmids\": [\"21725321\", \"22194622\", \"21873734\", \"22049082\", \"22002310\", \"21730126\", \"22159226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative importance of the many phosphorylation sites in integrating signals not systematically compared\", \"Tissue-specific weighting of nuclear vs. cytoplasmic functions still unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two studies revealed non-transcriptional signaling roles: Nur77 sequesters LKB1 in the nucleus to attenuate AMPK activation (reversed by the small molecule TMPA), and Nur77 forms a trimeric complex with TSC1/TSC2 that promotes TSC2 proteasomal degradation to activate mTORC1, driving cardiac hypertrophy.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, AMPK assays, compound binding, Nr4a1−/− mice; trimeric complex Co-IP, proteasome inhibition, cardiac hypertrophy models\",\n      \"pmids\": [\"22983157\", \"23197407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LKB1 sequestration and TSC2 degradation are coordinated or context-exclusive unknown\", \"Structural basis of trimeric TSC complex assembly not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"NR4A1's anti-inflammatory mechanism was directly demonstrated: it physically blocks p65 binding to κB elements, and LPS-activated p38α phosphorylation of Nur77 relieves this block; separately, Nr4a1 suppresses Runx3 transcription in CD8+ T cells by recruiting CoREST, modulating T cell differentiation.\",\n      \"evidence\": \"Co-IP, ChIP, phosphorylation assays, sepsis model; Nr4a1−/− mice, ChIP for CoREST, flow cytometry\",\n      \"pmids\": [\"25822914\", \"25762306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p38α phosphosite on Nur77 overlaps with other kinase sites\", \"CoREST recruitment mechanism to Runx3 not structurally resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The SUMO-ubiquitin degradation axis for NR4A1 was defined: PIAS3-mediated SUMO2/3 conjugation at two sites targets NR4A1 for RNF4-dependent polyubiquitination and proteasomal degradation, with SENP1 opposing this modification, providing a unified mechanism for post-translational Nur77 turnover that affects NF-κB signaling output.\",\n      \"evidence\": \"SUMOylation and ubiquitination assays, site-directed mutagenesis, PIAS3/SENP1 manipulation, NF-κB reporters\",\n      \"pmids\": [\"28622293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUMO-dependent degradation is coordinated with JNK/Ser95-dependent ubiquitination\", \"In vivo validation of SUMO-site mutants not performed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"NR4A1 was established as a metabolic regulator in macrophages (downregulating IDH to limit succinate accumulation and inflammatory output) and in hematopoietic stem cells (activating Cebpa via a hematopoietic-specific enhancer and antagonizing NF-κB to maintain quiescence).\",\n      \"evidence\": \"Nr4a1−/− macrophages with metabolomics and SDH epistasis; conditional NR4A1/NR4A3 double-KO with ChIP and gene profiling\",\n      \"pmids\": [\"30134173\", \"29343483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDH regulation is direct transcriptional or indirect\", \"NR4A1 versus NR4A3 individual contributions to HSC maintenance not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Ubiquitinated mitochondrial Nur77 was shown to undergo liquid-liquid phase separation, forming condensates through multivalent interactions between its N-terminal IDR and p62/SQSTM1 PB1 domain, coordinating mitophagy of damaged mitochondria—a fundamentally new biophysical mechanism for this receptor.\",\n      \"evidence\": \"In vitro phase separation reconstitution, domain mutagenesis, live-cell imaging, mitophagy flux assays\",\n      \"pmids\": [\"34645818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phase separation occurs in vivo under physiological (non-overexpression) conditions\", \"Ubiquitin chain type specificity for condensate formation not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies revealed unexpected non-nuclear functions: NR4A1 localizes to P-bodies in activated microglia where it directly binds and destabilizes Tnf mRNA in an m6A-dependent manner, and Mst1 kinase phosphorylates Nur77 at Thr-366 to enhance transcriptional activity and promote embryo implantation via β3-integrin.\",\n      \"evidence\": \"Conditional microglial Nr4a1 KO, RNA-binding assays, m6A analysis, P-body colocalization; in vitro kinase/LC-MS/MS, phospho-specific antibody, mouse implantation model\",\n      \"pmids\": [\"37486903\", \"36623453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Scope of NR4A1 RNA-binding targets beyond Tnf unknown\", \"Whether m6A-dependent RNA decay is a general NR4A1 function outside microglia not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of the Nur77–Bcl-2 and Nur77–p62 interactions, the hierarchy and crosstalk among the >8 documented phosphorylation events, the full spectrum of NR4A1 RNA targets, and how tissue-specific contexts select between its nuclear transcriptional, cytoplasmic signaling, mitochondrial apoptotic, and P-body RNA-regulatory functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of any NR4A1 complex\", \"Integrated phospho-signaling code not determined\", \"RNA targetome outside Tnf unknown\", \"Redundancy with NR4A2/NR4A3 incompletely resolved in most tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 4, 12, 17, 22, 28, 29, 30, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 4, 28, 36]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6, 15, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 4, 5, 6, 12, 17, 22, 28, 29, 30, 36]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 10, 11, 16, 40]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11, 16, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 7, 13, 16, 36, 37]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7, 8, 9, 29, 30, 31, 32, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 6, 11, 14, 17, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 4, 12, 22, 28, 29, 30, 36]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 9, 40]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [19, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BCL2\", \"RELA\", \"TP53\", \"SQSTM1\", \"FHL2\", \"PRMT1\", \"PIN1\", \"STK11\"],\n    \"other_free_text\": []\n  }\n}\n```"}