{"gene":"NCOA2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1996,"finding":"TIF2 (NCOA2) was cloned as a 160 kDa nuclear protein that interacts with nuclear receptors (NRs) in an agonist-dependent manner in vivo, binds directly to NR ligand-binding domains (LBDs) in an agonist- and AF-2-integrity-dependent manner in vitro, harbors an autonomous transcriptional activation function, relieves NR autosquelching, and enhances AF-2 activity when overexpressed in mammalian cells.","method":"Yeast two-hybrid, in vitro binding assays, mammalian transfection/reporter assays, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro binding, yeast two-hybrid, mammalian functional assays) in founding paper, subsequently widely replicated","pmids":["8670870"],"is_preprint":false},{"year":1998,"finding":"The TIF2 NR interaction domain (NID) contains three NR-box LxxLL motifs (boxes I, II, III); mutation of all three abrogates NR interaction and AF-2 stimulation. Box II alone is sufficient for efficient interaction with NR holo-LBDs. TIF2 activation domain AD1 mediates transactivation through CBP interaction, whereas AD2 acts independently of CBP.","method":"Mutational analysis, mammalian two-hybrid, yeast two-hybrid, transfection/reporter assays, dominant-negative peptide experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of all three NR boxes plus functional rescue assays; multiple orthogonal methods in single rigorous study","pmids":["9430642"],"is_preprint":false},{"year":1998,"finding":"All three NR boxes (LxxLL motifs) in the TIF2 receptor interaction domain (RID) are necessary and sufficient for interaction with nuclear hormone receptors; individual boxes show receptor-binding preferences. Cooperative binding of two TIF2 molecules to a heterodimeric NR complex occurs even when only one cognate ligand is present, indicating an allosteric effect.","method":"NR-box mutagenesis, in vitro binding assays, competition assays, pulldown experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis plus functional binding assays; single lab with multiple orthogonal methods","pmids":["9742117"],"is_preprint":false},{"year":1998,"finding":"The AF-2 activation domain core region of the androgen receptor (AR), specifically residue E888, is required for functional interaction with TIF2; the E888Q mutation markedly reduces TIF2-stimulated AR AF-2 activity without affecting hormone binding or LBD homodimerization.","method":"Mammalian cotransfection/reporter assays, yeast two-hybrid, site-directed mutagenesis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis combined with yeast two-hybrid and mammalian reporter assays; single lab but multiple orthogonal approaches","pmids":["9717843"],"is_preprint":false},{"year":1998,"finding":"MOZ-TIF2 fusion protein arises from inv(8)(p11q13) in AML; the predicted fusion retains MOZ histone acetyltransferase homology domains and the CBP-binding domain of TIF2, suggesting that aberrant recruitment of CBP by MOZ-TIF2 underlies the leukemia phenotype.","method":"FISH, Southern blotting, RT-PCR, structural analysis of fusion protein","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of fusion confirmed by multiple methods; mechanistic implication of CBP recruitment supported by domain analysis but not directly tested in this paper","pmids":["9558366"],"is_preprint":false},{"year":1999,"finding":"An AR mutation (M886V) in the LBD disrupts interdomain interactions (LBD–LBD, LBD–NTD) and impairs TIF2 binding, resulting in ~50% reduced transactivation capacity without altering ligand binding. The synthetic androgen mesterolone restores mutant LBD interactions with both the NTD and TIF2.","method":"Mammalian two-hybrid, yeast two-hybrid, reporter assays in multiple cell lines, steroid-binding assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — AR mutation characterized by multiple methods across three cell lines with mechanistic rescue by ligand analog","pmids":["10359561"],"is_preprint":false},{"year":2000,"finding":"TIF2 simultaneously interacts with both the isolated N-terminal AF1 domain and the C-terminal AF2 domain of ERα in transfected mammalian cells and in vitro, bridging both receptor domains to produce synergistic transcriptional activation. TIF2 mutants selectively deficient in AF1 or AF2 interaction were used to dissect the contributions of each AF.","method":"Mammalian two-hybrid, in vitro binding, reporter gene assays, TIF2 domain-selective mutants","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro and cell-based assays with engineered mutants; multiple orthogonal methods in single study","pmids":["11265755"],"is_preprint":false},{"year":2000,"finding":"AR mutation N727K in the LBD disrupts LBD interactions with the AR TAD and with TIF2 in mammalian and yeast two-hybrid assays, reducing transactivation to ~50% of wild-type without altering ligand binding; mesterolone (but not DHT) restores these interactions.","method":"Mammalian two-hybrid, yeast two-hybrid, reporter assays, steroid-binding assays","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary two-hybrid systems with ligand rescue experiment; single lab","pmids":["10935543"],"is_preprint":false},{"year":2001,"finding":"TIF2/GRIP1 functions as a corepressor (not only coactivator) at the collagenase-3 col3A response element: it is recruited to col3A and potentiates GR-mediated repression in the presence of GR agonist. GRIP1 mutants deficient in GR binding and coactivator functions were also defective for corepression; a GRIP1 fragment containing the GR-interacting region acted as a dominant-negative for repression. Repression by TR was unaffected by GRIP1.","method":"Chromatin immunoprecipitation, reporter assays, dominant-negative mutant analysis, co-factor recruitment assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP combined with functional reporter assays and domain-selective mutants establishing corepressor activity; single lab, multiple orthogonal methods","pmids":["11689447"],"is_preprint":false},{"year":2002,"finding":"PKA activation selectively down-regulates TIF2 protein levels (not mRNA) and impairs its coactivation of nuclear receptors including PPARα/γ and LXRα; the C-terminal activation domain AD2 of TIF2 is required for this inhibitory effect, suggesting AD2 is the target of PKA-mediated down-regulation.","method":"Transfection/reporter assays, Western blot, Northern blot, cotransfection with PKA catalytic subunit, TIF2 domain deletions","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping combined with functional assays and protein level analysis; single lab","pmids":["11923473"],"is_preprint":false},{"year":2002,"finding":"TIF2 mediates synergy between RARα1 AF-1 and AF-2 activation functions by bridging both domains; this interaction requires a motif in RARα1 region A and TIF2 AD1. Bridging is RAR isotype-selective (only RARα1) and not observed with SRC-1, demonstrating functional non-redundancy within the p160 family.","method":"Mammalian two-hybrid, reporter assays, domain-selective mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mammalian two-hybrid plus reporter assays; single lab, multiple approaches","pmids":["12149266"],"is_preprint":false},{"year":2002,"finding":"TIF2-deficient (TIF2−/−) mice are viable but display male hypofertility due to spermiogenesis defects (teratozoospermia) and age-dependent testicular degeneration from defective Sertoli cell–germ cell adhesion, and female hypofertility from placental hypoplasia in decidua stromal cells—demonstrating distinct, non-redundant physiological roles compared to SRC-1 and p/CIP knockouts.","method":"Targeted gene knockout (TIF2−/− mice), histological and reproductive phenotype analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with specific reproductive phenotypes characterized in detail; independently replicated by other groups","pmids":["12138202"],"is_preprint":false},{"year":2002,"finding":"TIF2−/− mice are protected against obesity and display enhanced adaptive thermogenesis. In white adipose tissue, lack of TIF2 decreases PPARγ activity and reduces fat accumulation; in brown adipose tissue, it facilitates the SRC-1–PGC-1α interaction that induces PGC-1α thermogenic activity. A high-fat diet increases the TIF2/SRC-1 ratio, contributing to weight gain.","method":"Knockout mouse model, metabolic phenotyping, co-immunoprecipitation of SRC-1 and PGC-1α, reporter assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse combined with co-IP and functional assays; published in high-impact journal and widely cited","pmids":["12507421"],"is_preprint":false},{"year":2003,"finding":"MOZ-TIF2 has transforming properties in vitro and causes AML in a murine bone marrow transplant model. The C2HC nucleosome recognition motif of MOZ is essential for transformation (MOZ HAT activity is dispensable), and TIF2-mediated interaction with CBP through the TIF2 CBP interaction domain (CID/AD1) is essential for transformation—demonstrating that nucleosomal targeting by MOZ plus CBP recruitment by TIF2 are both required.","method":"Murine bone marrow transplant assay, in vitro transformation (colony formation), domain-deletion mutants of MOZ-TIF2","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo AML model combined with systematic domain mutant analysis; widely replicated","pmids":["12676584"],"is_preprint":false},{"year":2003,"finding":"β-catenin binds to the AR ligand-binding domain (AF-2 region) in a ligand agonist-dependent manner, independently of and cooperatively with TIF2 and the AR NTD (both of which also bind AF-2). AR, β-catenin, and TIF2 form a three-way interaction that mediates ligand-dependent transcription; distinct helix-12 mutations selectively disrupt β-catenin but not TIF2/NTD binding.","method":"Mammalian two-hybrid, co-immunoprecipitation, reporter gene assays, mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP combined with two-hybrid, reporter assays, and systematic mutagenesis; single lab but multiple orthogonal methods","pmids":["12588987"],"is_preprint":false},{"year":2004,"finding":"SRC-1 partially compensates for TIF2 loss in survival and growth; in Sertoli cells, SRC-1 and TIF2 perform redundant functions—inactivation of SRC-1 alleles in TIF2-null background uniformly accelerates and worsens testicular degeneration, establishing functional redundancy in this cell type.","method":"SRC-1/TIF2 compound-mutant mouse analysis, histological and reproductive phenotype characterization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via compound knockout mice with clear phenotypic rescue/worsening readout","pmids":["15070739"],"is_preprint":false},{"year":2004,"finding":"TIF2 forms nuclear foci in the absence of glucocorticoid receptor (GR); upon GR agonist (but not antagonist) treatment, GR is recruited to TIF2 foci. Coactivators p300 and PCAF are also recruited to TIF2 foci, and a microinjected GR-responsive element (GRE) is recruited to these foci—suggesting TIF2 provides a pre-formed nuclear compartment for GR transcriptional complex assembly.","method":"Immunofluorescence/live imaging, microinjection of fluorescent GRE, nuclear fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (ligand-dependent GR recruitment), single lab","pmids":["15207724"],"is_preprint":false},{"year":2005,"finding":"MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent transcriptional activators (nuclear receptors, p53). This requires the TIF2 CBP-binding domain (AD1); co-IP and FRET show MOZ-TIF2 interacts with CBP directly in vivo. MOZ-TIF2 displays aberrant nuclear distribution, reduces cellular CBP levels, and depletes CBP from PML bodies.","method":"Co-immunoprecipitation, FRET, reporter assays, immunofluorescence, Western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal co-IP plus FRET plus localization and functional assays; single lab with multiple orthogonal methods","pmids":["15657427"],"is_preprint":false},{"year":2005,"finding":"β-catenin binds directly to TIF2/GRIP1 (both N- and C-terminal regions of β-catenin required), and β-catenin can mediate binding between TIF2 and AR in a three-way complex. A β-catenin C-terminal peptide (229 aa) binds both TIF2 and AR but acts as a dominant inhibitor of ligand-dependent transcription.","method":"Co-immunoprecipitation, mammalian two-hybrid, reporter assays, dominant-negative peptide","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional reporter assays; single lab","pmids":["16141201"],"is_preprint":false},{"year":2006,"finding":"STAMP (TTLL5), a newly identified 1,277-aa protein, associates with TIF2 (and SRC-1), is selective for a subset of steroid/nuclear receptors including GR, and modulates TIF2 effects in both GR-mediated gene induction and repression. Endogenous STAMP colocalizes with GR in intact cells and is recruited to promoters of GR-regulated genes.","method":"Co-immunoprecipitation, siRNA knockdown of endogenous genes, ChIP, transfection/reporter assays, immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, siRNA knockdown of endogenous genes, and localization; multiple orthogonal methods in single study","pmids":["17116691"],"is_preprint":false},{"year":2007,"finding":"An N-terminal fragment of TIF2 (TIF2.0, aa 1–627) competes with corepressors NCoR/SMRT for binding to GR and PR. This TIF2 N-terminal region binds an N-terminal GR region; for PR-B an N-terminal sequence largely absent in PR-A is necessary but not sufficient. NCoR RID#1 (not RID#2) is required for binding to both GR and PR agonist/antagonist complexes. ChIP shows exogenous TIF2.0 reduces PRE-associated NCoR.","method":"Mammalian two-hybrid, pulldown, co-immunoprecipitation, ChIP, NCoR mutagenesis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods plus ChIP; single lab","pmids":["17571860"],"is_preprint":false},{"year":2008,"finding":"Absence of SRC-2 (NCOA2) in mice causes a glycogenopathy resembling Von Gierke's disease. SRC-2 controls fasting hepatic glucose release by coactivating the orphan nuclear receptor RORα to regulate glucose-6-phosphatase (G6Pase) expression; both whole-body and liver-specific SRC-2 ablation produce this phenotype.","method":"Whole-body and liver-specific knockout mice, metabolic phenotyping, reporter/coactivation assays with RORα, ChIP","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific and whole-body knockouts with defined molecular mechanism (RORα coactivation of G6Pase), published in Science","pmids":["19039140"],"is_preprint":false},{"year":2009,"finding":"IL-6-treated LNCaP cells upregulate TIF2 levels and become resistant to bicalutamide. ShRNA knockdown of TIF2 in IL-6-treated cells re-sensitizes them to bicalutamide, while TIF2 overexpression in parental cells confers resistance. IL-6/TIF2 attenuates bicalutamide-mediated blockade of androgen-induced AR nuclear translocation and chromatin recruitment.","method":"shRNA knockdown, overexpression, nuclear translocation assay, ChIP, cell viability assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with mechanistic readout (AR nuclear translocation/recruitment); single lab","pmids":["19240160"],"is_preprint":false},{"year":2009,"finding":"cAMP/PKA signaling enhances ERRα interaction with SRC-2 at the SP-A promoter in lung type II cells. SRC-2 has the most pronounced effect among tested coactivators in increasing ERRα transcriptional activity at the SP-A promoter; this is enhanced by PKA catalytic subunit. Three ERRα serines (S87, S114, S277) are critical for PKA and SRC-2 induction of ERRα activity.","method":"Reporter assays, co-immunoprecipitation, ChIP, site-directed mutagenesis, pharmacological inhibitors","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, mutagenesis, and pharmacological experiments; single lab","pmids":["19264843"],"is_preprint":false},{"year":2010,"finding":"MOZ-TIF2 and MOZ-CBP fusion proteins interact with the transcription factor PU.1 to stimulate CSF1R (M-CSFR) expression; PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells. Cells with high CSF1R expression contain the leukemia-initiating activity, and CSF1R inhibitors slow MOZ-TIF2-induced leukemia progression.","method":"Co-immunoprecipitation, PU.1-deficient mouse studies, transgenic suicide-gene mouse model, CSF1R inhibitor treatment, serial transplantation","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of protein interaction, genetic epistasis (PU.1 knockout), in vivo pharmacological validation; multiple orthogonal methods","pmids":["20418886"],"is_preprint":false},{"year":2010,"finding":"Conditional ablation of TIF2 in skeletal muscle myofibers (TIF2(i)skm−/− mice) increases mitochondrial uncoupling, protects against sedentariness-induced metabolic decline, delays type 2 diabetes, and attenuates diet-induced obesity. SRC-1 and TIF2 antagonistically modulate UCP3 expression in skeletal muscle: loss of TIF2 elevates SRC-1, which upregulates UCP3.","method":"Conditional knockout mice (inducible, muscle-specific), metabolic and mitochondrial phenotyping, gene expression analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional knockout with defined molecular mechanism (SRC-1/UCP3 regulation); multiple phenotypic readouts","pmids":["21035760"],"is_preprint":false},{"year":2011,"finding":"SRC-2 and SRC-3 (but not SRC-1) are required for human adipocyte differentiation: knockdown of SRC-2 or SRC-3 (individually or jointly) inhibits lipid accumulation and lipogenic gene expression without affecting PPARγ protein levels. SRC-2/SRC-3 knockdown increases inhibitory PPARγ-S114 phosphorylation, revealing a mechanism by which these coactivators promote adipogenesis.","method":"siRNA knockdown, high-content analysis (single-cell quantification), lipid staining, phospho-PPARγ immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative single-cell loss-of-function with specific phosphorylation mechanism; single lab","pmids":["21220509"],"is_preprint":false},{"year":2012,"finding":"The N-terminal fragment of TIF2 (TIF2.0) binds the intrinsically disordered GR AF1 domain, increasing its α-helical content. TIF2 coactivator activity is observed in the absence of the GR LBD in an AF1-dependent manner, establishing that TIF2 can directly modify AF1 structure and activity without requiring LBD interaction.","method":"Circular dichroism, hydrogen-deuterium exchange mass spectrometry, cell-based reporter assays, domain-deletion constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biophysical structure determination (CD) combined with functional assays; single lab but multiple orthogonal methods including HDX-MS","pmids":["23132854"],"is_preprint":false},{"year":2012,"finding":"SRC-2 ablation activates the 'fetal gene program' in adult mouse heart (shifts in metabolic and sarcomeric gene expression). SRC-2 knockout mice exhibit decreased functional reserve under pressure overload (transverse aortic constriction), blunted ventricular hypertrophic response, and impaired hypertrophic signaling.","method":"Knockout mice, genome-wide microarray, targeted gene expression, echocardiography, transverse aortic constriction model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotypic readout and gene expression mechanism; single lab","pmids":["23300926"],"is_preprint":false},{"year":2012,"finding":"Transposon mutagenesis screen (Sleeping Beauty) identified Ncoa2/Src-2 as a tumor suppressor cooperating with MYC in liver cancer. RNAi-mediated knockdown of Ncoa2 in liver progenitor cells accelerates tumor development, and Ncoa2 deletion in mice predisposes to diethylnitrosamine-induced liver tumorigenesis.","method":"Sleeping Beauty transposon mutagenesis screen, RNAi knockdown, carcinogen-induced tumorigenesis in KO mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — forward genetic screen validated by KO mouse and RNAi; single lab","pmids":["22556267"],"is_preprint":false},{"year":2013,"finding":"PAX3-NCOA2 fusion protein promotes proliferation and inhibits myogenic differentiation of rhabdomyosarcoma cells. In C2C12 cells, PAX3-NCOA2 accelerates G1/S progression, increases motility, enhances anchorage-independent growth, and increases transcriptional activation of PAX3 consensus-binding sites, but causes weaker differentiation block than PAX3-FOXO1A.","method":"Stable cell line expression, proliferation/motility/anchorage-independence assays, cell cycle analysis, reporter assays, nude mouse xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in cell line and xenograft with defined readouts; single lab","pmids":["24213582"],"is_preprint":false},{"year":2013,"finding":"MOZ-TIF2 forms a stable complex with BRPF1 (a component of the MOZ complex); MOZ-TIF2 and BRPF1 co-occupy HOX gene promoters in AML cells. BRPF1 depletion reduces MOZ localization on HOX genes and abolishes MOZ-TIF2 transformation. MOZ-TIF2 lacking HAT activity cannot deregulate HOX genes or initiate leukemia, establishing that MOZ HAT-dependent histone acetylation via the MOZ-TIF2/BRPF1 complex is required for HOX upregulation and AML.","method":"Co-immunoprecipitation, ChIP, shRNA depletion, HAT-mutant MOZ-TIF2, colony-forming assay, AML mouse model","journal":"International journal of hematology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of complex, ChIP of genomic occupancy, loss-of-function (BRPF1 depletion + HAT mutant), in vivo AML model; multiple orthogonal methods","pmids":["24258712"],"is_preprint":false},{"year":2014,"finding":"SRC-2 (NCOA2) drives glutamine-dependent de novo lipogenesis in prostate cancer cells via reductive carboxylation of α-ketoglutarate through retrograde TCA cycling. Glutamine-mediated mTORC1 signaling activates SRC-2 through mTORC1-dependent phosphorylation; activated SRC-2 then coactivates SREBP-1 to enhance lipogenic enzyme expression.","method":"Metabolic profiling (isotope tracing), co-immunoprecipitation (SRC-2/SREBP-1), siRNA/shRNA knockdown, murine tumor xenograft models, ChIP","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — metabolic flux experiments, co-IP, in vivo mouse models, and ChIP in multiple experimental systems; replicated across model systems","pmids":["25664849"],"is_preprint":false},{"year":2014,"finding":"Androgen deprivation induces NCoA2 (SRC-2) expression; NCoA2 overexpression in murine prostate causes neoplasia and, combined with PTEN deletion, promotes metastasis-prone cancer. NCoA2 overexpression in prostate tumors results in hyperactivation of PI3K/AKT and MAPK signaling. NCoA2 depletion in PTEN-deficient mice prevents CRPC development.","method":"Conditional transgenic overexpression, conditional KO (NCoA2 depletion in PTEN-null mice), signaling pathway analysis (Western blot), human tissue correlation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function and loss-of-function mouse models with defined signaling mechanism (PI3K/AKT, MAPK hyperactivation); multiple genetic models","pmids":["25295534"],"is_preprint":false},{"year":2014,"finding":"SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK heterodimer in the mammalian circadian clock. Genome-wide ChIP shows diurnal SRC-2 recruitment that extensively overlaps with the BMAL1 cistrome. SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in peripheral tissues, disrupts rhythmicity of the hepatic metabolome, and SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop.","method":"Genome-wide ChIP-seq, SRC-2 knockout mice, behavioral assays, metabolomic profiling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq genome-wide occupancy combined with KO behavioral and metabolic phenotypes; multiple orthogonal methods","pmids":["24529706"],"is_preprint":false},{"year":2015,"finding":"NCOA2 inhibits Wnt/β-catenin signaling in colorectal cancer by simultaneously upregulating inhibitors and downregulating stimulators of the Wnt/β-catenin pathway. Enforced expression of wild-type NCOA2 (but not the LACTB2-NCOA2 fusion protein) impairs pro-tumorigenic phenotypes, whereas NCOA2 knockdown in normal colonocytes has opposite effects.","method":"Forced expression and shRNA knockdown, reporter assays, colony formation, xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined pathway (Wnt/β-catenin); single lab","pmids":["25823027"],"is_preprint":false},{"year":2015,"finding":"Metformin transcriptionally suppresses SRC-2 mRNA, reducing SRC-2 and RNA polymerase II recruitment to the G6Pc promoter and to SRE-containing promoters of lipid/cholesterol biosynthesis genes. SRC-2 is identified as a coactivator of SREBP-1 at the FASN promoter via transactivation assays.","method":"Reporter/transactivation assays, ChIP, microarray, qRT-PCR, knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays establishing SREBP-1 coactivation mechanism; single lab","pmids":["26548416"],"is_preprint":false},{"year":2015,"finding":"NcoA2 inhibits HIF-1α activation via AhR. NcoA2 overexpression downregulates HRE transactivation by competing with HIF-1α and AhR to form protein complexes with ARNT. NcoA2 knockdown also inhibits HRE transactivation. NcoA2 and HIF-1α nuclear localization decrease in AhR-knockdown cells, and NcoA2 regulates angiogenesis in vitro and in vivo.","method":"Reporter assays, co-immunoprecipitation, knockdown/overexpression, in vitro tube formation assay, in vivo plug assay, immunofluorescence","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, reporter assays, and in vivo angiogenesis; single lab with multiple methods","pmids":["26350169"],"is_preprint":false},{"year":2015,"finding":"SRC-2 orchestrates transcriptional complexes controlling rate-limiting steps of hepatic glucose release and accretion. DNA pull-down coupled with mass spectrometry identified SRC-2 as an integrator of nutritionally responsive transcriptional complexes; SRC-2 modulates both glucose storage (glycogen) and release programs in liver.","method":"DNA pull-down with mass spectrometry, ChIP, reporter assays, KO mouse metabolic phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification of complexes plus KO phenotype and ChIP; single lab","pmids":["26487680"],"is_preprint":false},{"year":2017,"finding":"SRC-2 directly activates a set of anti-tumorigenic target genes (SHP, DKK4, CADM4) that suppress MYC-driven liver tumorigenesis. In vivo ChIP-seq in Src-2−/−/MYC liver tumors shows reduced SRC-2 occupancy at these gene promoters; enforced expression of SHP, DKK4, or CADM4 suppresses tumorigenesis in vitro and in vivo.","method":"ChIP-seq, RNA-seq, KO mouse tumor model, in vitro and in vivo functional rescue experiments","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus KO mouse model and rescue experiments identifying direct target genes; multiple orthogonal methods","pmids":["28273073"],"is_preprint":false},{"year":2018,"finding":"Ring1A and Ring1B (PRC1 components) maintain MOZ-TIF2 AML stem cells by repressing Glis2 expression. Deletion of Ring1A/B from MOZ-TIF2 AML cells diminishes self-renewal and induces Glis2 expression; Glis2 overexpression drives differentiation of MOZ-TIF2 AML cells, while Glis2 knockdown in Ring1A/B-deficient cells inhibits differentiation.","method":"Conditional deletion of Ring1A/B in mouse AML model, gene expression analysis, Glis2 overexpression/knockdown, colony-forming and differentiation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis (Ring1A/B deletion epistatic to Glis2) with defined differentiation readout; single lab","pmids":["29371181"],"is_preprint":false},{"year":2018,"finding":"SRC-2 is required for the full transcriptional response to progesterone receptor (PGR) during human endometrial stromal cell (hESC) decidualization. ChIP-seq and RNA-seq identify the SRC-2-dependent decidualization transcriptome; >50% of SRC-2-regulated genes are also PGR-regulated. SRC-2 is specifically required for induction of the retinol transporter STRA6 during decidualization.","method":"ChIP-seq, RNA-seq, siRNA knockdown in primary hESCs, reporter assays","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq combined with functional knockdown; single lab","pmids":["30325183"],"is_preprint":false},{"year":2019,"finding":"NCOA2 physically interacts with the KSHV replication and transcription activator (RTA) in vitro and in vivo, binding the PARS II domain of RTA. NCOA2 enhances RTA protein stability by competing with the E3 ubiquitin ligase MDM2 for PARS II binding, preventing proteasome-mediated RTA degradation and promoting KSHV lytic reactivation. RTA in turn upregulates NCOA2 expression, forming a positive feedback loop.","method":"Co-immunoprecipitation, in vitro binding assay, proteasome inhibition assay, overexpression/knockdown in KSHV-infected cells, lytic gene expression analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro and in vivo co-IP, competition assay with MDM2, gain- and loss-of-function in infected cells; multiple orthogonal methods in single study","pmids":["31751430"],"is_preprint":false},{"year":2021,"finding":"PFKFB4 phosphorylates SRC-2 at Ser487, altering SRC-2 transcriptional activity. Co-immunoprecipitation demonstrates PFKFB4–SRC-2 interaction. PFKFB4-mediated SRC-2 phosphorylation promotes lung adenocarcinoma cell proliferation, migration, and invasion; downstream transcriptomics identifies CARM1 as a transcriptional target of SRC-2 involved in this axis.","method":"Co-immunoprecipitation, Western blot (phospho-Ser487), siRNA knockdown, overexpression, transcriptome sequencing, cell proliferation/migration/invasion assays","journal":"BMC pulmonary medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus phosphorylation site identification plus functional assays; single lab","pmids":["33593309"],"is_preprint":false},{"year":2021,"finding":"NMR and X-ray crystallographic data reveal that the TIF2 nuclear receptor interaction domain (TIF2NRID) is largely disordered with partially structured NR-box regions. All three NR-boxes and their flanking regions engage RXR/RAR in a multisite binding mode, with flanking regions playing an active role; the protein adopts a more structured conformation upon receptor binding.","method":"NMR, SAXS, X-ray crystallography, SEC-MALS, Far-UV CD — structural characterization of TIF2NRID alone and in complex with RXR/RAR","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution structural methods (NMR + X-ray crystallography) combined with biophysical validation; single study with multiple orthogonal structural techniques","pmids":["33647291"],"is_preprint":false},{"year":2022,"finding":"HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets (as determined by ChIP-seq), resulting in transactivation of these targets and significant enhancement of cell proliferation in iPSC-derived MSCs. HEY1-NCOA2 (but not wild-type HEY1 or NCOA2 alone) directly targets and upregulates PDGFB and PDGFRA, dramatically increasing phospho-AKT (Ser473).","method":"ChIP-seq, RNA-seq, iPSC-derived MSC model with inducible expression, Western blot (phospho-AKT)","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genome-wide ChIP-seq and RNA-seq with mechanistic validation (AKT phosphorylation); fusion-specific effects confirmed against WT controls","pmids":["35342947"],"is_preprint":false},{"year":2022,"finding":"ETV6-NCOA2 forms a transcriptional complex with ETV6 and histone acetyltransferase p300, leading to derepression of ETV6 target genes. Expression in nonthymic hematopoietic progenitors (mouse BM and human CD34+ cord blood) induces T/myeloid leukemia by activating a lymphoid program while failing to repress myeloid genes (CSF1, MEF2C); co-acquisition of activating NOTCH1 mutations is required for full leukemic transformation.","method":"Co-immunoprecipitation (ETV6-NCOA2/ETV6/p300 complex), ChIP, mouse BM transduction/transplantation model, human cord blood xenograft model, gene expression profiling","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP establishing complex, ChIP, and two independent in vivo leukemia models (mouse and human); multiple orthogonal methods with mechanistic insight","pmids":["34624096"],"is_preprint":false},{"year":2023,"finding":"Ncoa2 promotes CD8+ T cell activation and antitumor immunity by upregulating PGC-1α expression to enhance mitochondrial biogenesis and function. T-cell activation-induced CREB phosphorylation triggers Ncoa2 recruitment to PGC-1α enhancers. T cell-specific Ncoa2 knockout (Ncoa2fl/fl/CD4Cre) causes defective mitochondrial mass increase, impaired oxidative phosphorylation, reduced IFNγ, and failure to reject tumors. Forced PGC-1α expression rescues these defects.","method":"Conditional T cell-specific KO mice, ChIP (CREB-induced Ncoa2 enhancer recruitment), mitochondrial functional assays, adoptive transfer tumor rejection, PGC-1α rescue experiment","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP, mitochondrial function assays, adoptive transfer, and genetic rescue; multiple orthogonal methods establishing mechanistic pathway","pmids":["37540802"],"is_preprint":false},{"year":2023,"finding":"HEY1-NCOA2 expression in mouse embryonic superficial zone cells induces mesenchymal chondrosarcoma with biphasic morphology. HEY1-NCOA2 interacts with Runx2 (via NCOA2 C-terminal domains) and enhances chondrocyte differentiation gene programs; ChIP-seq shows frequent interaction between HEY1-NCOA2 binding peaks and active enhancers. Runx2 knockout delays tumor onset but induces aggressive small round cell growth. HDAC inhibitor panobinostat suppresses tumor growth by abrogating HEY1-NCOA2/Runx2 downstream gene expression.","method":"Mouse tumor model, ChIP-seq, co-immunoprecipitation (HEY1-NCOA2/Runx2), HDAC inhibitor treatment, gene expression analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse tumor model, co-IP, ChIP-seq, genetic epistasis (Runx2 KO), and pharmacological validation; multiple orthogonal methods","pmids":["37212282"],"is_preprint":false},{"year":2024,"finding":"KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein itself are necessary for indefinite proliferation of MOZ-TIF2 AML cells; pharmacological inhibition or targeted protein degradation of KAT6 activity abolishes this. MOZ-TIF2 directly regulates a small subset of developmental transcription factor genes, and transcription levels correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr).","method":"Pharmacological KAT6 inhibition, targeted protein degradation (PROTAC), histone modification profiling (H3K23pr), ChIP, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic inhibition combined with targeted degradation, ChIP, and histone modification analysis; multiple mechanistic approaches in single study","pmids":["38889153"],"is_preprint":false}],"current_model":"NCOA2 (TIF2/SRC-2) is a p160 family transcriptional coactivator that binds liganded nuclear receptor ligand-binding domains via three LxxLL NR-box motifs in its receptor interaction domain; its AD1 region recruits CBP/p300 while AD2 acts independently, and it can also directly bind and structurally reorganize the intrinsically disordered AF1 domain of steroid receptors. Beyond nuclear receptor coactivation, NCOA2 serves as a coactivator for BMAL1:CLOCK circadian oscillators, SREBP-1, and RORα in metabolic gene regulation; it is phosphorylated by mTORC1 and PFKFB4 to modulate its transcriptional activity; in CD8+ T cells it is recruited to the PGC-1α enhancer by CREB to support mitochondrial biogenesis and antitumor immunity; and recurrent fusion with MOZ creates an oncogenic complex that requires both MOZ nucleosomal targeting and TIF2-mediated CBP recruitment (via AD1) to transform hematopoietic progenitors into leukemic stem cells, while fusions with HEY1 (in mesenchymal chondrosarcoma), ETV6, PAX3, SRF, TEAD1, AHRR, VGLL2, and MEIS1 drive distinct sarcoma and leukemia subtypes."},"narrative":{"mechanistic_narrative":"NCOA2 (TIF2/SRC-2/GRIP1) is a p160-family transcriptional coactivator that couples liganded nuclear receptors to the general transcription machinery and chromatin-modifying enzymes [PMID:8670870, PMID:9430642]. It engages agonist-bound receptor ligand-binding domains through three LxxLL NR-box motifs in an intrinsically disordered receptor-interaction domain that becomes structured upon receptor engagement, with flanking sequences contributing to a multisite binding mode [PMID:9430642, PMID:33647291]; its AD1 region transactivates by recruiting CBP/p300 while AD2 acts independently [PMID:9430642]. Beyond classical LBD binding, NCOA2 directly binds and increases the α-helical content of the disordered AF1 domain of steroid receptors, and can bridge receptor AF1 and AF2 surfaces to produce synergistic activation [PMID:11265755, PMID:23132854]. Context determines its output: NCOA2 also acts as a corepressor at glucocorticoid-repressed genes [PMID:11689447], and integrates upstream signaling through PKA-dependent destabilization [PMID:11923473], mTORC1-dependent phosphorylation [PMID:25664849], and PFKFB4-mediated Ser487 phosphorylation [PMID:33593309]. Knockout mice establish non-redundant physiological roles in reproduction [PMID:12138202], adaptive thermogenesis and obesity resistance [PMID:12507421, PMID:21035760], and hepatic glucose homeostasis, where NCOA2 coactivates RORα to control glucose-6-phosphatase and prevents a Von Gierke-like glycogenopathy [PMID:19039140]. NCOA2 further serves as a coactivator of the BMAL1:CLOCK circadian oscillator [PMID:24529706] and of SREBP-1 in lipogenesis [PMID:25664849, PMID:26548416], and supports CD8+ T-cell antitumor immunity by CREB-directed recruitment to the PGC-1α enhancer to drive mitochondrial biogenesis [PMID:37540802]. In cancer, NCOA2 behaves as both a tumor suppressor (cooperating against MYC-driven liver tumorigenesis) [PMID:22556267, PMID:28273073] and an oncogenic driver, most notably as a recurrent fusion partner: the MOZ-TIF2 fusion transforms hematopoietic progenitors by combining MOZ nucleosomal targeting and HAT activity with TIF2/AD1-mediated CBP recruitment [PMID:9558366, PMID:12676584, PMID:24258712], and fusions with HEY1, ETV6, and PAX3 drive mesenchymal chondrosarcoma, leukemia, and rhabdomyosarcoma respectively [PMID:35342947, PMID:34624096, PMID:24213582].","teleology":[{"year":1996,"claim":"Established NCOA2 as a bona fide nuclear receptor coactivator, defining the core activity from which all later functions derive — that it binds agonist-bound receptor LBDs and autonomously activates transcription.","evidence":"Cloning with yeast two-hybrid, in vitro LBD binding, and mammalian reporter assays","pmids":["8670870"],"confidence":"High","gaps":["Did not map the binding motifs or the activation domains","No endogenous target genes identified"]},{"year":1998,"claim":"Resolved the molecular grammar of receptor engagement and transactivation by mapping three LxxLL NR-boxes for receptor binding and separating AD1 (CBP-dependent) from AD2 (CBP-independent) activation surfaces.","evidence":"Systematic NR-box mutagenesis, two-hybrid, reporter and dominant-negative peptide assays across two studies","pmids":["9430642","9742117"],"confidence":"High","gaps":["Structural basis of NR-box selectivity not resolved","How AD2 activates transcription mechanistically unknown"]},{"year":1998,"claim":"Connected coactivator recruitment to receptor surface integrity and identified the oncogenic MOZ-TIF2 fusion, framing both physiological AF-2 dependence and a disease-relevant rearrangement.","evidence":"AR AF-2 residue mutagenesis (E888) plus FISH/RT-PCR characterization of inv(8) fusion","pmids":["9717843","9558366"],"confidence":"High","gaps":["Fusion oncogenicity not functionally tested at this stage","AF-2 contact mode inferred from mutants only"]},{"year":2000,"claim":"Showed NCOA2 bridges receptor AF1 and AF2 domains to drive synergy, extending its action beyond LBD docking and revealing isotype-selective, p160-non-redundant bridging.","evidence":"Mammalian two-hybrid, in vitro binding, and domain-selective mutants on ERα and RARα1","pmids":["11265755","12149266"],"confidence":"High","gaps":["Structural mechanism of dual-domain bridging unresolved","Generality across receptors untested"]},{"year":2001,"claim":"Demonstrated NCOA2 can act as a corepressor at specific glucocorticoid-repressed genes, establishing that its transcriptional output is context-dependent rather than uniformly activating.","evidence":"ChIP, reporter and dominant-negative mutant analysis at the col3A response element","pmids":["11689447"],"confidence":"High","gaps":["Repression mechanism / partner enzymes not defined","Promoter determinants of activator-vs-repressor switch unknown"]},{"year":2002,"claim":"Defined upstream signal control and the first physiological roles, showing PKA destabilizes NCOA2 via AD2 and that loss in mice produces distinct reproductive and metabolic phenotypes.","evidence":"PKA cotransfection with domain deletions; TIF2-null mouse reproductive and metabolic phenotyping with co-IP of SRC-1/PGC-1α","pmids":["11923473","12138202","12507421"],"confidence":"High","gaps":["PKA does not phosphorylate a defined NCOA2 residue here","Tissue-specific target genes not fully resolved"]},{"year":2003,"claim":"Proved MOZ-TIF2 is leukemogenic in vivo and dissected the required modules — MOZ nucleosome recognition plus TIF2/AD1-mediated CBP recruitment — converting an associative fusion into a mechanistic oncogene.","evidence":"Murine bone marrow transplant AML model with systematic domain-deletion mutants; β-catenin/AR/TIF2 three-way complex by co-IP and two-hybrid","pmids":["12676584","12588987"],"confidence":"High","gaps":["Direct target genes of MOZ-TIF2 not yet identified at this stage","MOZ HAT role appeared dispensable here but revisited later"]},{"year":2004,"claim":"Established p160 functional redundancy and a nuclear-compartment model, showing SRC-1 compensates in Sertoli cells and that TIF2 forms pre-assembled foci that recruit GR and coactivators upon ligand.","evidence":"SRC-1/TIF2 compound-mutant mice; immunofluorescence/live imaging with microinjected GRE","pmids":["15070739","15207724"],"confidence":"High","gaps":["Molecular basis of foci formation undefined","Degree of redundancy across other tissues unknown"]},{"year":2005,"claim":"Clarified the dominant-negative mechanism of MOZ-TIF2 and a β-catenin bridging route, showing the fusion sequesters CBP via AD1 and depletes it from PML bodies.","evidence":"Reciprocal co-IP, FRET, immunofluorescence and reporter assays; β-catenin/TIF2/AR co-IP and dominant-negative peptide","pmids":["15657427","16141201"],"confidence":"High","gaps":["How CBP sequestration translates to specific gene deregulation unresolved","β-catenin bridging significance in vivo untested"]},{"year":2007,"claim":"Identified accessory regulators and a corepressor-competition mechanism, showing an N-terminal NCOA2 fragment competes with NCoR/SMRT for receptor binding and that STAMP/TTLL5 modulates NCOA2 output.","evidence":"Two-hybrid, pulldown, co-IP, ChIP, siRNA of endogenous STAMP, NCoR mutagenesis (two studies)","pmids":["17116691","17571860"],"confidence":"Medium","gaps":["Functional significance of NCoR competition at endogenous genes limited","STAMP/TTLL5 enzymatic contribution to NCOA2 regulation unclear"]},{"year":2008,"claim":"Defined a discrete metabolic function in hepatic glucose release, linking NCOA2 to RORα coactivation of G6Pase and revealing a glycogenopathy phenotype on its loss.","evidence":"Whole-body and liver-specific knockout mice with metabolic phenotyping, RORα coactivation and ChIP","pmids":["19039140"],"confidence":"High","gaps":["Full hepatic complex composition not yet mapped","Signal that activates NCOA2 during fasting undefined here"]},{"year":2010,"claim":"Extended the muscle/metabolism axis and the leukemia mechanism, showing TIF2 antagonizes SRC-1/UCP3 in muscle and that MOZ-TIF2 requires PU.1 to drive CSF1R for leukemia stem-cell maintenance.","evidence":"Inducible muscle-specific knockout with metabolic phenotyping; co-IP, PU.1-deficient mice, CSF1R inhibitor, serial transplantation","pmids":["21035760","20418886"],"confidence":"High","gaps":["Mechanism of SRC-1/TIF2 antagonism at UCP3 not fully defined","How PU.1 cooperates structurally with the fusion unknown"]},{"year":2012,"claim":"Defined NCOA2's role in adipogenesis and the biophysics of AF1 engagement, showing it can directly fold the disordered GR AF1 and that it suppresses inhibitory PPARγ-S114 phosphorylation; also revealed a tumor-suppressor role in liver.","evidence":"siRNA single-cell adipocyte assays; CD and HDX-MS on GR AF1; cardiac and Sleeping Beauty/MYC liver tumor models","pmids":["21220509","23132854","23300926","22556267"],"confidence":"High","gaps":["Structural detail of the NCOA2-AF1 complex not at residue resolution","Tumor-suppressor target genes not yet identified at this stage"]},{"year":2013,"claim":"Refined MOZ-TIF2 leukemogenesis to require MOZ HAT activity via a BRPF1-containing complex at HOX genes, and identified PAX3-NCOA2 as a rhabdomyosarcoma driver.","evidence":"Co-IP, ChIP, shRNA, HAT-mutant fusion and AML model; PAX3-NCOA2 cell-line and xenograft assays","pmids":["24258712","24213582"],"confidence":"High","gaps":["Reconciliation with earlier HAT-dispensable finding context-dependent","PAX3-NCOA2 endogenous target genes not mapped"]},{"year":2014,"claim":"Established NCOA2 as a circadian and oncogenic metabolic hub, coactivating BMAL1:CLOCK genome-wide and, downstream of mTORC1, SREBP-1 to drive glutamine-fueled lipogenesis and prostate cancer.","evidence":"ChIP-seq with KO behavioral/metabolomic phenotyping; isotope tracing, co-IP, xenografts and prostate GOF/LOF mouse models","pmids":["24529706","25664849","25295534"],"confidence":"High","gaps":["mTORC1-phosphorylated NCOA2 residue not pinpointed here","Crosstalk between circadian and lipogenic programs unexplored"]},{"year":2015,"claim":"Expanded NCOA2's regulatory range to Wnt/β-catenin suppression, SREBP-1-driven lipid/glucose genes (metformin target), and HIF-1α/AhR competition controlling angiogenesis.","evidence":"GOF/LOF reporter, ChIP and xenograft assays across colorectal, hepatic and angiogenesis models","pmids":["25823027","26548416","26350169","26487680"],"confidence":"Medium","gaps":["Direct vs indirect pathway effects not always separated","Mechanism of ARNT-competition not structurally defined"]},{"year":2017,"claim":"Identified the direct anti-tumorigenic target genes (SHP, DKK4, CADM4) through which NCOA2 suppresses MYC-driven liver cancer, giving molecular substance to its tumor-suppressor role.","evidence":"In vivo ChIP-seq, RNA-seq, KO tumor model and functional rescue with individual target genes","pmids":["28273073"],"confidence":"High","gaps":["Receptor/partner directing NCOA2 to these promoters not defined","Why the same coactivator is oncogenic elsewhere unresolved"]},{"year":2018,"claim":"Defined the decidualization transcriptome and refined leukemic fusion mechanism, showing NCOA2 is required for full PGR response in endometrium and that ETV6-NCOA2 recruits p300 to derepress ETV6 targets.","evidence":"ChIP-seq/RNA-seq with siRNA in primary hESCs; co-IP, ChIP and mouse/human leukemia models; Ring1A/B-Glis2 epistasis in AML","pmids":["30325183","34624096","29371181"],"confidence":"Medium","gaps":["NOTCH1 cooperativity mechanism with ETV6-NCOA2 incomplete","PRC1 link to NCOA2-fusion chromatin state indirect"]},{"year":2019,"claim":"Revealed a non-transcriptional, virology role: NCOA2 stabilizes the KSHV RTA protein by competing with MDM2, promoting lytic reactivation through a positive feedback loop.","evidence":"In vitro and in vivo co-IP, MDM2 competition and proteasome assays, GOF/LOF in infected cells","pmids":["31751430"],"confidence":"High","gaps":["Whether NCOA2 stabilizes other clients similarly unknown","Structural basis of PARS II binding not resolved"]},{"year":2021,"claim":"Pinpointed signaling control and the disordered structural basis of receptor recognition, identifying PFKFB4-mediated Ser487 phosphorylation and resolving the multisite NR-box binding mode by NMR/crystallography.","evidence":"Co-IP, phospho-Ser487 immunoblot and functional assays; NMR, SAXS, X-ray and SEC-MALS of TIF2NRID with RXR/RAR","pmids":["33593309","33647291"],"confidence":"High","gaps":["Functional consequence of disorder-to-order transition in cells untested","How distinct phosphorylations integrate combinatorially unknown"]},{"year":2022,"claim":"Mechanistically resolved the HEY1-NCOA2 chondrosarcoma fusion, showing it occupies canonical HEY1 promoters and upregulates PDGFB/PDGFRA to activate AKT signaling.","evidence":"ChIP-seq, RNA-seq, inducible iPSC-derived MSC model and phospho-AKT immunoblot","pmids":["35342947"],"confidence":"High","gaps":["NCOA2 moiety's coactivator contribution to fusion activity not isolated","Therapeutic targetability of the PDGF axis untested here"]},{"year":2023,"claim":"Defined NCOA2's role in immunometabolism and chondrosarcoma in vivo, showing CREB-directed recruitment to the PGC-1α enhancer drives CD8+ T-cell mitochondrial biogenesis and that HEY1-NCOA2 cooperates with Runx2, an HDAC-inhibitor-sensitive program.","evidence":"T-cell conditional KO with ChIP, mitochondrial assays, adoptive transfer and PGC-1α rescue; mouse chondrosarcoma model with co-IP, ChIP-seq, Runx2 KO and panobinostat","pmids":["37540802","37212282"],"confidence":"High","gaps":["Nuclear receptor partner in the T-cell PGC-1α axis not identified","Runx2-independent fusion programs incompletely defined"]},{"year":2024,"claim":"Confirmed KAT6 enzymatic dependence of MOZ-TIF2 AML and linked the fusion to histone H3K23 propionylation at a small set of developmental transcription factor genes, defining a druggable enzymatic node.","evidence":"Pharmacological KAT6 inhibition and PROTAC degradation, H3K23pr profiling, ChIP and gene expression analysis","pmids":["38889153"],"confidence":"High","gaps":["Functional role of H3K23pr versus acetylation not separated","Which target genes are the essential drivers undefined"]},{"year":null,"claim":"It remains unresolved how a single coactivator integrates its many phosphorylation inputs (PKA, mTORC1, PFKFB4) and partner contexts to switch between activator, corepressor, tumor-suppressor and oncogenic-fusion behaviors at specific loci.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking post-translational state to genomic target selection","Structural basis of context-dependent activator/repressor switching unknown","Endogenous full coactivator complex composition across tissues incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,21,34,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,8,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,13,46]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,16]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[16,17]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,21,25,32]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,13,30,45,46]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,32,43,47]}],"complexes":["MOZ-TIF2/BRPF1 complex","BMAL1:CLOCK coactivator complex","ETV6-NCOA2/p300 complex"],"partners":["CREBBP","EP300","CTNNB1","AR","ESR1","BMAL1","SREBF1","TTLL5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15596","full_name":"Nuclear receptor coactivator 2","aliases":["Class E basic helix-loop-helix protein 75","bHLHe75","Transcriptional intermediary factor 2","hTIF2"],"length_aa":1464,"mass_kda":159.2,"function":"Transcriptional coactivator for steroid receptors and nuclear receptors (PubMed:23508108, PubMed:8670870, PubMed:9430642, PubMed:22504882, PubMed:26553876). Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1) (PubMed:23508108, PubMed:8670870, PubMed:9430642). Required with NCOA1 to control energy balance between white and brown adipose tissues (PubMed:23508108, PubMed:8670870, PubMed:9430642). Critical regulator of glucose metabolism regulation, acts as a RORA coactivator to specifically modulate G6PC1 expression (PubMed:23508108, PubMed:8670870, PubMed:9430642). Involved in the positive regulation of the transcriptional activity of the glucocorticoid receptor NR3C1 by sumoylation enhancer RWDD3 (PubMed:23508108). Positively regulates the circadian clock by acting as a transcriptional coactivator for the CLOCK-BMAL1 heterodimer (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15596/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NCOA2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NCOA2","total_profiled":1310},"omim":[{"mim_id":"618921","title":"LACTAMASE, BETA-2; LACTB2","url":"https://www.omim.org/entry/618921"},{"mim_id":"614610","title":"KN MOTIF- AND ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 2; KANK2","url":"https://www.omim.org/entry/614610"},{"mim_id":"612268","title":"TUBULIN TYROSINE LIGASE-LIKE 5; TTLL5","url":"https://www.omim.org/entry/612268"},{"mim_id":"611421","title":"SNF2-RELATED CBP ACTIVATOR PROTEIN; SRCAP","url":"https://www.omim.org/entry/611421"},{"mim_id":"611371","title":"ZINC FINGER PROTEIN 653; ZNF653","url":"https://www.omim.org/entry/611371"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCOA2"},"hgnc":{"alias_symbol":["SRC-2","TIF2","GRIP1","NCoA-2","KAT13C","bHLHe75"],"prev_symbol":[]},"alphafold":{"accession":"Q15596","domains":[{"cath_id":"-","chopping":"37-89","consensus_level":"medium","plddt":80.0677,"start":37,"end":89},{"cath_id":"3.30.450.20","chopping":"114-180_195-208_223-237_246-260","consensus_level":"medium","plddt":84.8508,"start":114,"end":260},{"cath_id":"3.30.450.20","chopping":"269-376","consensus_level":"high","plddt":89.8973,"start":269,"end":376}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15596","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15596-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15596-F1-predicted_aligned_error_v6.png","plddt_mean":47.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCOA2","jax_strain_url":"https://www.jax.org/strain/search?query=NCOA2"},"sequence":{"accession":"Q15596","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15596.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15596/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15596"}},"corpus_meta":[{"pmid":"8670870","id":"PMC_8670870","title":"TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8670870","citation_count":904,"is_preprint":false},{"pmid":"15607963","id":"PMC_15607963","title":"MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors.","date":"2004","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/15607963","citation_count":532,"is_preprint":false},{"pmid":"9238002","id":"PMC_9238002","title":"RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9238002","citation_count":495,"is_preprint":false},{"pmid":"9430642","id":"PMC_9430642","title":"The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates 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Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/34166279","citation_count":13,"is_preprint":false},{"pmid":"23707616","id":"PMC_23707616","title":"Expression and characterization of androgen receptor coregulators, SRC-2 and HBO1, during human testis ontogenesis and in androgen signaling deficient patients.","date":"2013","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23707616","citation_count":13,"is_preprint":false},{"pmid":"38889153","id":"PMC_38889153","title":"A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38889153","citation_count":12,"is_preprint":false},{"pmid":"26854485","id":"PMC_26854485","title":"Expression of the MOZ-TIF2 oncoprotein in mice represses senescence.","date":"2016","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/26854485","citation_count":12,"is_preprint":false},{"pmid":"26261634","id":"PMC_26261634","title":"Association of NCOA2 gene polymorphisms with obesity and dyslipidemia in the Chinese Han population.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26261634","citation_count":12,"is_preprint":false},{"pmid":"36811835","id":"PMC_36811835","title":"Aggressive High-grade Uterine Sarcoma Harboring MEIS1-NCOA2 Fusion and Amplification of Multiple 12q13-15 Genes: A Case Report With Morphologic, Immunohistochemical, and Molecular Analysis.","date":"2023","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/36811835","citation_count":12,"is_preprint":false},{"pmid":"12150973","id":"PMC_12150973","title":"Coactivation of an endogenous progesterone receptor by TIF2 in COS-7 cells.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12150973","citation_count":12,"is_preprint":false},{"pmid":"19277704","id":"PMC_19277704","title":"Estrogen signaling in colorectal carcinoma microenvironment: expression of ERbeta1, AIB-1, and TIF-2 is upregulated in cancer-associated myofibroblasts and correlates with disease progression.","date":"2009","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19277704","citation_count":12,"is_preprint":false},{"pmid":"25202377","id":"PMC_25202377","title":"Primary spinal intradural mesenchymal chondrosarcoma with detection of fusion gene HEY1-NCOA2: A paediatric case report and review of the literature.","date":"2014","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25202377","citation_count":12,"is_preprint":false},{"pmid":"32410572","id":"PMC_32410572","title":"SRC-2 Coactivator: a role in human metabolic evolution and disease.","date":"2020","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/32410572","citation_count":11,"is_preprint":false},{"pmid":"37668330","id":"PMC_37668330","title":"Intraosseous Spindle Cell Rhabdomyosarcoma with MEIS1::NCOA2 Fusion - Case Report with Substantial Clinical Follow-up and Review of the Literature.","date":"2023","source":"Cancer investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37668330","citation_count":11,"is_preprint":false},{"pmid":"26487680","id":"PMC_26487680","title":"SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26487680","citation_count":11,"is_preprint":false},{"pmid":"22342989","id":"PMC_22342989","title":"Separate regions of glucocorticoid receptor, coactivator TIF2, and comodulator STAMP modify different parameters of glucocorticoid-mediated gene induction.","date":"2012","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22342989","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49796,"output_tokens":12793,"usd":0.170642,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24818,"output_tokens":7349,"usd":0.153908,"stage2_stop_reason":"end_turn"},"total_usd":0.32455,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"TIF2 (NCOA2) was cloned as a 160 kDa nuclear protein that interacts with nuclear receptors (NRs) in an agonist-dependent manner in vivo, binds directly to NR ligand-binding domains (LBDs) in an agonist- and AF-2-integrity-dependent manner in vitro, harbors an autonomous transcriptional activation function, relieves NR autosquelching, and enhances AF-2 activity when overexpressed in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, mammalian transfection/reporter assays, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro binding, yeast two-hybrid, mammalian functional assays) in founding paper, subsequently widely replicated\",\n      \"pmids\": [\"8670870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The TIF2 NR interaction domain (NID) contains three NR-box LxxLL motifs (boxes I, II, III); mutation of all three abrogates NR interaction and AF-2 stimulation. Box II alone is sufficient for efficient interaction with NR holo-LBDs. TIF2 activation domain AD1 mediates transactivation through CBP interaction, whereas AD2 acts independently of CBP.\",\n      \"method\": \"Mutational analysis, mammalian two-hybrid, yeast two-hybrid, transfection/reporter assays, dominant-negative peptide experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of all three NR boxes plus functional rescue assays; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"9430642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"All three NR boxes (LxxLL motifs) in the TIF2 receptor interaction domain (RID) are necessary and sufficient for interaction with nuclear hormone receptors; individual boxes show receptor-binding preferences. Cooperative binding of two TIF2 molecules to a heterodimeric NR complex occurs even when only one cognate ligand is present, indicating an allosteric effect.\",\n      \"method\": \"NR-box mutagenesis, in vitro binding assays, competition assays, pulldown experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis plus functional binding assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9742117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The AF-2 activation domain core region of the androgen receptor (AR), specifically residue E888, is required for functional interaction with TIF2; the E888Q mutation markedly reduces TIF2-stimulated AR AF-2 activity without affecting hormone binding or LBD homodimerization.\",\n      \"method\": \"Mammalian cotransfection/reporter assays, yeast two-hybrid, site-directed mutagenesis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis combined with yeast two-hybrid and mammalian reporter assays; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"9717843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MOZ-TIF2 fusion protein arises from inv(8)(p11q13) in AML; the predicted fusion retains MOZ histone acetyltransferase homology domains and the CBP-binding domain of TIF2, suggesting that aberrant recruitment of CBP by MOZ-TIF2 underlies the leukemia phenotype.\",\n      \"method\": \"FISH, Southern blotting, RT-PCR, structural analysis of fusion protein\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of fusion confirmed by multiple methods; mechanistic implication of CBP recruitment supported by domain analysis but not directly tested in this paper\",\n      \"pmids\": [\"9558366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"An AR mutation (M886V) in the LBD disrupts interdomain interactions (LBD–LBD, LBD–NTD) and impairs TIF2 binding, resulting in ~50% reduced transactivation capacity without altering ligand binding. The synthetic androgen mesterolone restores mutant LBD interactions with both the NTD and TIF2.\",\n      \"method\": \"Mammalian two-hybrid, yeast two-hybrid, reporter assays in multiple cell lines, steroid-binding assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — AR mutation characterized by multiple methods across three cell lines with mechanistic rescue by ligand analog\",\n      \"pmids\": [\"10359561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIF2 simultaneously interacts with both the isolated N-terminal AF1 domain and the C-terminal AF2 domain of ERα in transfected mammalian cells and in vitro, bridging both receptor domains to produce synergistic transcriptional activation. TIF2 mutants selectively deficient in AF1 or AF2 interaction were used to dissect the contributions of each AF.\",\n      \"method\": \"Mammalian two-hybrid, in vitro binding, reporter gene assays, TIF2 domain-selective mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro and cell-based assays with engineered mutants; multiple orthogonal methods in single study\",\n      \"pmids\": [\"11265755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AR mutation N727K in the LBD disrupts LBD interactions with the AR TAD and with TIF2 in mammalian and yeast two-hybrid assays, reducing transactivation to ~50% of wild-type without altering ligand binding; mesterolone (but not DHT) restores these interactions.\",\n      \"method\": \"Mammalian two-hybrid, yeast two-hybrid, reporter assays, steroid-binding assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary two-hybrid systems with ligand rescue experiment; single lab\",\n      \"pmids\": [\"10935543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIF2/GRIP1 functions as a corepressor (not only coactivator) at the collagenase-3 col3A response element: it is recruited to col3A and potentiates GR-mediated repression in the presence of GR agonist. GRIP1 mutants deficient in GR binding and coactivator functions were also defective for corepression; a GRIP1 fragment containing the GR-interacting region acted as a dominant-negative for repression. Repression by TR was unaffected by GRIP1.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter assays, dominant-negative mutant analysis, co-factor recruitment assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP combined with functional reporter assays and domain-selective mutants establishing corepressor activity; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11689447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PKA activation selectively down-regulates TIF2 protein levels (not mRNA) and impairs its coactivation of nuclear receptors including PPARα/γ and LXRα; the C-terminal activation domain AD2 of TIF2 is required for this inhibitory effect, suggesting AD2 is the target of PKA-mediated down-regulation.\",\n      \"method\": \"Transfection/reporter assays, Western blot, Northern blot, cotransfection with PKA catalytic subunit, TIF2 domain deletions\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping combined with functional assays and protein level analysis; single lab\",\n      \"pmids\": [\"11923473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2 mediates synergy between RARα1 AF-1 and AF-2 activation functions by bridging both domains; this interaction requires a motif in RARα1 region A and TIF2 AD1. Bridging is RAR isotype-selective (only RARα1) and not observed with SRC-1, demonstrating functional non-redundancy within the p160 family.\",\n      \"method\": \"Mammalian two-hybrid, reporter assays, domain-selective mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mammalian two-hybrid plus reporter assays; single lab, multiple approaches\",\n      \"pmids\": [\"12149266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2-deficient (TIF2−/−) mice are viable but display male hypofertility due to spermiogenesis defects (teratozoospermia) and age-dependent testicular degeneration from defective Sertoli cell–germ cell adhesion, and female hypofertility from placental hypoplasia in decidua stromal cells—demonstrating distinct, non-redundant physiological roles compared to SRC-1 and p/CIP knockouts.\",\n      \"method\": \"Targeted gene knockout (TIF2−/− mice), histological and reproductive phenotype analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with specific reproductive phenotypes characterized in detail; independently replicated by other groups\",\n      \"pmids\": [\"12138202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2−/− mice are protected against obesity and display enhanced adaptive thermogenesis. In white adipose tissue, lack of TIF2 decreases PPARγ activity and reduces fat accumulation; in brown adipose tissue, it facilitates the SRC-1–PGC-1α interaction that induces PGC-1α thermogenic activity. A high-fat diet increases the TIF2/SRC-1 ratio, contributing to weight gain.\",\n      \"method\": \"Knockout mouse model, metabolic phenotyping, co-immunoprecipitation of SRC-1 and PGC-1α, reporter assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse combined with co-IP and functional assays; published in high-impact journal and widely cited\",\n      \"pmids\": [\"12507421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MOZ-TIF2 has transforming properties in vitro and causes AML in a murine bone marrow transplant model. The C2HC nucleosome recognition motif of MOZ is essential for transformation (MOZ HAT activity is dispensable), and TIF2-mediated interaction with CBP through the TIF2 CBP interaction domain (CID/AD1) is essential for transformation—demonstrating that nucleosomal targeting by MOZ plus CBP recruitment by TIF2 are both required.\",\n      \"method\": \"Murine bone marrow transplant assay, in vitro transformation (colony formation), domain-deletion mutants of MOZ-TIF2\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo AML model combined with systematic domain mutant analysis; widely replicated\",\n      \"pmids\": [\"12676584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"β-catenin binds to the AR ligand-binding domain (AF-2 region) in a ligand agonist-dependent manner, independently of and cooperatively with TIF2 and the AR NTD (both of which also bind AF-2). AR, β-catenin, and TIF2 form a three-way interaction that mediates ligand-dependent transcription; distinct helix-12 mutations selectively disrupt β-catenin but not TIF2/NTD binding.\",\n      \"method\": \"Mammalian two-hybrid, co-immunoprecipitation, reporter gene assays, mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP combined with two-hybrid, reporter assays, and systematic mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12588987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SRC-1 partially compensates for TIF2 loss in survival and growth; in Sertoli cells, SRC-1 and TIF2 perform redundant functions—inactivation of SRC-1 alleles in TIF2-null background uniformly accelerates and worsens testicular degeneration, establishing functional redundancy in this cell type.\",\n      \"method\": \"SRC-1/TIF2 compound-mutant mouse analysis, histological and reproductive phenotype characterization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via compound knockout mice with clear phenotypic rescue/worsening readout\",\n      \"pmids\": [\"15070739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIF2 forms nuclear foci in the absence of glucocorticoid receptor (GR); upon GR agonist (but not antagonist) treatment, GR is recruited to TIF2 foci. Coactivators p300 and PCAF are also recruited to TIF2 foci, and a microinjected GR-responsive element (GRE) is recruited to these foci—suggesting TIF2 provides a pre-formed nuclear compartment for GR transcriptional complex assembly.\",\n      \"method\": \"Immunofluorescence/live imaging, microinjection of fluorescent GRE, nuclear fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (ligand-dependent GR recruitment), single lab\",\n      \"pmids\": [\"15207724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent transcriptional activators (nuclear receptors, p53). This requires the TIF2 CBP-binding domain (AD1); co-IP and FRET show MOZ-TIF2 interacts with CBP directly in vivo. MOZ-TIF2 displays aberrant nuclear distribution, reduces cellular CBP levels, and depletes CBP from PML bodies.\",\n      \"method\": \"Co-immunoprecipitation, FRET, reporter assays, immunofluorescence, Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal co-IP plus FRET plus localization and functional assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15657427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"β-catenin binds directly to TIF2/GRIP1 (both N- and C-terminal regions of β-catenin required), and β-catenin can mediate binding between TIF2 and AR in a three-way complex. A β-catenin C-terminal peptide (229 aa) binds both TIF2 and AR but acts as a dominant inhibitor of ligand-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, mammalian two-hybrid, reporter assays, dominant-negative peptide\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional reporter assays; single lab\",\n      \"pmids\": [\"16141201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STAMP (TTLL5), a newly identified 1,277-aa protein, associates with TIF2 (and SRC-1), is selective for a subset of steroid/nuclear receptors including GR, and modulates TIF2 effects in both GR-mediated gene induction and repression. Endogenous STAMP colocalizes with GR in intact cells and is recruited to promoters of GR-regulated genes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of endogenous genes, ChIP, transfection/reporter assays, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, siRNA knockdown of endogenous genes, and localization; multiple orthogonal methods in single study\",\n      \"pmids\": [\"17116691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"An N-terminal fragment of TIF2 (TIF2.0, aa 1–627) competes with corepressors NCoR/SMRT for binding to GR and PR. This TIF2 N-terminal region binds an N-terminal GR region; for PR-B an N-terminal sequence largely absent in PR-A is necessary but not sufficient. NCoR RID#1 (not RID#2) is required for binding to both GR and PR agonist/antagonist complexes. ChIP shows exogenous TIF2.0 reduces PRE-associated NCoR.\",\n      \"method\": \"Mammalian two-hybrid, pulldown, co-immunoprecipitation, ChIP, NCoR mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods plus ChIP; single lab\",\n      \"pmids\": [\"17571860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Absence of SRC-2 (NCOA2) in mice causes a glycogenopathy resembling Von Gierke's disease. SRC-2 controls fasting hepatic glucose release by coactivating the orphan nuclear receptor RORα to regulate glucose-6-phosphatase (G6Pase) expression; both whole-body and liver-specific SRC-2 ablation produce this phenotype.\",\n      \"method\": \"Whole-body and liver-specific knockout mice, metabolic phenotyping, reporter/coactivation assays with RORα, ChIP\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific and whole-body knockouts with defined molecular mechanism (RORα coactivation of G6Pase), published in Science\",\n      \"pmids\": [\"19039140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-6-treated LNCaP cells upregulate TIF2 levels and become resistant to bicalutamide. ShRNA knockdown of TIF2 in IL-6-treated cells re-sensitizes them to bicalutamide, while TIF2 overexpression in parental cells confers resistance. IL-6/TIF2 attenuates bicalutamide-mediated blockade of androgen-induced AR nuclear translocation and chromatin recruitment.\",\n      \"method\": \"shRNA knockdown, overexpression, nuclear translocation assay, ChIP, cell viability assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with mechanistic readout (AR nuclear translocation/recruitment); single lab\",\n      \"pmids\": [\"19240160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"cAMP/PKA signaling enhances ERRα interaction with SRC-2 at the SP-A promoter in lung type II cells. SRC-2 has the most pronounced effect among tested coactivators in increasing ERRα transcriptional activity at the SP-A promoter; this is enhanced by PKA catalytic subunit. Three ERRα serines (S87, S114, S277) are critical for PKA and SRC-2 induction of ERRα activity.\",\n      \"method\": \"Reporter assays, co-immunoprecipitation, ChIP, site-directed mutagenesis, pharmacological inhibitors\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, mutagenesis, and pharmacological experiments; single lab\",\n      \"pmids\": [\"19264843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MOZ-TIF2 and MOZ-CBP fusion proteins interact with the transcription factor PU.1 to stimulate CSF1R (M-CSFR) expression; PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells. Cells with high CSF1R expression contain the leukemia-initiating activity, and CSF1R inhibitors slow MOZ-TIF2-induced leukemia progression.\",\n      \"method\": \"Co-immunoprecipitation, PU.1-deficient mouse studies, transgenic suicide-gene mouse model, CSF1R inhibitor treatment, serial transplantation\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of protein interaction, genetic epistasis (PU.1 knockout), in vivo pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"20418886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Conditional ablation of TIF2 in skeletal muscle myofibers (TIF2(i)skm−/− mice) increases mitochondrial uncoupling, protects against sedentariness-induced metabolic decline, delays type 2 diabetes, and attenuates diet-induced obesity. SRC-1 and TIF2 antagonistically modulate UCP3 expression in skeletal muscle: loss of TIF2 elevates SRC-1, which upregulates UCP3.\",\n      \"method\": \"Conditional knockout mice (inducible, muscle-specific), metabolic and mitochondrial phenotyping, gene expression analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional knockout with defined molecular mechanism (SRC-1/UCP3 regulation); multiple phenotypic readouts\",\n      \"pmids\": [\"21035760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRC-2 and SRC-3 (but not SRC-1) are required for human adipocyte differentiation: knockdown of SRC-2 or SRC-3 (individually or jointly) inhibits lipid accumulation and lipogenic gene expression without affecting PPARγ protein levels. SRC-2/SRC-3 knockdown increases inhibitory PPARγ-S114 phosphorylation, revealing a mechanism by which these coactivators promote adipogenesis.\",\n      \"method\": \"siRNA knockdown, high-content analysis (single-cell quantification), lipid staining, phospho-PPARγ immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative single-cell loss-of-function with specific phosphorylation mechanism; single lab\",\n      \"pmids\": [\"21220509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The N-terminal fragment of TIF2 (TIF2.0) binds the intrinsically disordered GR AF1 domain, increasing its α-helical content. TIF2 coactivator activity is observed in the absence of the GR LBD in an AF1-dependent manner, establishing that TIF2 can directly modify AF1 structure and activity without requiring LBD interaction.\",\n      \"method\": \"Circular dichroism, hydrogen-deuterium exchange mass spectrometry, cell-based reporter assays, domain-deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical structure determination (CD) combined with functional assays; single lab but multiple orthogonal methods including HDX-MS\",\n      \"pmids\": [\"23132854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRC-2 ablation activates the 'fetal gene program' in adult mouse heart (shifts in metabolic and sarcomeric gene expression). SRC-2 knockout mice exhibit decreased functional reserve under pressure overload (transverse aortic constriction), blunted ventricular hypertrophic response, and impaired hypertrophic signaling.\",\n      \"method\": \"Knockout mice, genome-wide microarray, targeted gene expression, echocardiography, transverse aortic constriction model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotypic readout and gene expression mechanism; single lab\",\n      \"pmids\": [\"23300926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transposon mutagenesis screen (Sleeping Beauty) identified Ncoa2/Src-2 as a tumor suppressor cooperating with MYC in liver cancer. RNAi-mediated knockdown of Ncoa2 in liver progenitor cells accelerates tumor development, and Ncoa2 deletion in mice predisposes to diethylnitrosamine-induced liver tumorigenesis.\",\n      \"method\": \"Sleeping Beauty transposon mutagenesis screen, RNAi knockdown, carcinogen-induced tumorigenesis in KO mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — forward genetic screen validated by KO mouse and RNAi; single lab\",\n      \"pmids\": [\"22556267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAX3-NCOA2 fusion protein promotes proliferation and inhibits myogenic differentiation of rhabdomyosarcoma cells. In C2C12 cells, PAX3-NCOA2 accelerates G1/S progression, increases motility, enhances anchorage-independent growth, and increases transcriptional activation of PAX3 consensus-binding sites, but causes weaker differentiation block than PAX3-FOXO1A.\",\n      \"method\": \"Stable cell line expression, proliferation/motility/anchorage-independence assays, cell cycle analysis, reporter assays, nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in cell line and xenograft with defined readouts; single lab\",\n      \"pmids\": [\"24213582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MOZ-TIF2 forms a stable complex with BRPF1 (a component of the MOZ complex); MOZ-TIF2 and BRPF1 co-occupy HOX gene promoters in AML cells. BRPF1 depletion reduces MOZ localization on HOX genes and abolishes MOZ-TIF2 transformation. MOZ-TIF2 lacking HAT activity cannot deregulate HOX genes or initiate leukemia, establishing that MOZ HAT-dependent histone acetylation via the MOZ-TIF2/BRPF1 complex is required for HOX upregulation and AML.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA depletion, HAT-mutant MOZ-TIF2, colony-forming assay, AML mouse model\",\n      \"journal\": \"International journal of hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of complex, ChIP of genomic occupancy, loss-of-function (BRPF1 depletion + HAT mutant), in vivo AML model; multiple orthogonal methods\",\n      \"pmids\": [\"24258712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRC-2 (NCOA2) drives glutamine-dependent de novo lipogenesis in prostate cancer cells via reductive carboxylation of α-ketoglutarate through retrograde TCA cycling. Glutamine-mediated mTORC1 signaling activates SRC-2 through mTORC1-dependent phosphorylation; activated SRC-2 then coactivates SREBP-1 to enhance lipogenic enzyme expression.\",\n      \"method\": \"Metabolic profiling (isotope tracing), co-immunoprecipitation (SRC-2/SREBP-1), siRNA/shRNA knockdown, murine tumor xenograft models, ChIP\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — metabolic flux experiments, co-IP, in vivo mouse models, and ChIP in multiple experimental systems; replicated across model systems\",\n      \"pmids\": [\"25664849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Androgen deprivation induces NCoA2 (SRC-2) expression; NCoA2 overexpression in murine prostate causes neoplasia and, combined with PTEN deletion, promotes metastasis-prone cancer. NCoA2 overexpression in prostate tumors results in hyperactivation of PI3K/AKT and MAPK signaling. NCoA2 depletion in PTEN-deficient mice prevents CRPC development.\",\n      \"method\": \"Conditional transgenic overexpression, conditional KO (NCoA2 depletion in PTEN-null mice), signaling pathway analysis (Western blot), human tissue correlation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function and loss-of-function mouse models with defined signaling mechanism (PI3K/AKT, MAPK hyperactivation); multiple genetic models\",\n      \"pmids\": [\"25295534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK heterodimer in the mammalian circadian clock. Genome-wide ChIP shows diurnal SRC-2 recruitment that extensively overlaps with the BMAL1 cistrome. SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in peripheral tissues, disrupts rhythmicity of the hepatic metabolome, and SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop.\",\n      \"method\": \"Genome-wide ChIP-seq, SRC-2 knockout mice, behavioral assays, metabolomic profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq genome-wide occupancy combined with KO behavioral and metabolic phenotypes; multiple orthogonal methods\",\n      \"pmids\": [\"24529706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NCOA2 inhibits Wnt/β-catenin signaling in colorectal cancer by simultaneously upregulating inhibitors and downregulating stimulators of the Wnt/β-catenin pathway. Enforced expression of wild-type NCOA2 (but not the LACTB2-NCOA2 fusion protein) impairs pro-tumorigenic phenotypes, whereas NCOA2 knockdown in normal colonocytes has opposite effects.\",\n      \"method\": \"Forced expression and shRNA knockdown, reporter assays, colony formation, xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined pathway (Wnt/β-catenin); single lab\",\n      \"pmids\": [\"25823027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Metformin transcriptionally suppresses SRC-2 mRNA, reducing SRC-2 and RNA polymerase II recruitment to the G6Pc promoter and to SRE-containing promoters of lipid/cholesterol biosynthesis genes. SRC-2 is identified as a coactivator of SREBP-1 at the FASN promoter via transactivation assays.\",\n      \"method\": \"Reporter/transactivation assays, ChIP, microarray, qRT-PCR, knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays establishing SREBP-1 coactivation mechanism; single lab\",\n      \"pmids\": [\"26548416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NcoA2 inhibits HIF-1α activation via AhR. NcoA2 overexpression downregulates HRE transactivation by competing with HIF-1α and AhR to form protein complexes with ARNT. NcoA2 knockdown also inhibits HRE transactivation. NcoA2 and HIF-1α nuclear localization decrease in AhR-knockdown cells, and NcoA2 regulates angiogenesis in vitro and in vivo.\",\n      \"method\": \"Reporter assays, co-immunoprecipitation, knockdown/overexpression, in vitro tube formation assay, in vivo plug assay, immunofluorescence\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, reporter assays, and in vivo angiogenesis; single lab with multiple methods\",\n      \"pmids\": [\"26350169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRC-2 orchestrates transcriptional complexes controlling rate-limiting steps of hepatic glucose release and accretion. DNA pull-down coupled with mass spectrometry identified SRC-2 as an integrator of nutritionally responsive transcriptional complexes; SRC-2 modulates both glucose storage (glycogen) and release programs in liver.\",\n      \"method\": \"DNA pull-down with mass spectrometry, ChIP, reporter assays, KO mouse metabolic phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification of complexes plus KO phenotype and ChIP; single lab\",\n      \"pmids\": [\"26487680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRC-2 directly activates a set of anti-tumorigenic target genes (SHP, DKK4, CADM4) that suppress MYC-driven liver tumorigenesis. In vivo ChIP-seq in Src-2−/−/MYC liver tumors shows reduced SRC-2 occupancy at these gene promoters; enforced expression of SHP, DKK4, or CADM4 suppresses tumorigenesis in vitro and in vivo.\",\n      \"method\": \"ChIP-seq, RNA-seq, KO mouse tumor model, in vitro and in vivo functional rescue experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus KO mouse model and rescue experiments identifying direct target genes; multiple orthogonal methods\",\n      \"pmids\": [\"28273073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ring1A and Ring1B (PRC1 components) maintain MOZ-TIF2 AML stem cells by repressing Glis2 expression. Deletion of Ring1A/B from MOZ-TIF2 AML cells diminishes self-renewal and induces Glis2 expression; Glis2 overexpression drives differentiation of MOZ-TIF2 AML cells, while Glis2 knockdown in Ring1A/B-deficient cells inhibits differentiation.\",\n      \"method\": \"Conditional deletion of Ring1A/B in mouse AML model, gene expression analysis, Glis2 overexpression/knockdown, colony-forming and differentiation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis (Ring1A/B deletion epistatic to Glis2) with defined differentiation readout; single lab\",\n      \"pmids\": [\"29371181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRC-2 is required for the full transcriptional response to progesterone receptor (PGR) during human endometrial stromal cell (hESC) decidualization. ChIP-seq and RNA-seq identify the SRC-2-dependent decidualization transcriptome; >50% of SRC-2-regulated genes are also PGR-regulated. SRC-2 is specifically required for induction of the retinol transporter STRA6 during decidualization.\",\n      \"method\": \"ChIP-seq, RNA-seq, siRNA knockdown in primary hESCs, reporter assays\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq combined with functional knockdown; single lab\",\n      \"pmids\": [\"30325183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NCOA2 physically interacts with the KSHV replication and transcription activator (RTA) in vitro and in vivo, binding the PARS II domain of RTA. NCOA2 enhances RTA protein stability by competing with the E3 ubiquitin ligase MDM2 for PARS II binding, preventing proteasome-mediated RTA degradation and promoting KSHV lytic reactivation. RTA in turn upregulates NCOA2 expression, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, proteasome inhibition assay, overexpression/knockdown in KSHV-infected cells, lytic gene expression analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro and in vivo co-IP, competition assay with MDM2, gain- and loss-of-function in infected cells; multiple orthogonal methods in single study\",\n      \"pmids\": [\"31751430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PFKFB4 phosphorylates SRC-2 at Ser487, altering SRC-2 transcriptional activity. Co-immunoprecipitation demonstrates PFKFB4–SRC-2 interaction. PFKFB4-mediated SRC-2 phosphorylation promotes lung adenocarcinoma cell proliferation, migration, and invasion; downstream transcriptomics identifies CARM1 as a transcriptional target of SRC-2 involved in this axis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot (phospho-Ser487), siRNA knockdown, overexpression, transcriptome sequencing, cell proliferation/migration/invasion assays\",\n      \"journal\": \"BMC pulmonary medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus phosphorylation site identification plus functional assays; single lab\",\n      \"pmids\": [\"33593309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMR and X-ray crystallographic data reveal that the TIF2 nuclear receptor interaction domain (TIF2NRID) is largely disordered with partially structured NR-box regions. All three NR-boxes and their flanking regions engage RXR/RAR in a multisite binding mode, with flanking regions playing an active role; the protein adopts a more structured conformation upon receptor binding.\",\n      \"method\": \"NMR, SAXS, X-ray crystallography, SEC-MALS, Far-UV CD — structural characterization of TIF2NRID alone and in complex with RXR/RAR\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution structural methods (NMR + X-ray crystallography) combined with biophysical validation; single study with multiple orthogonal structural techniques\",\n      \"pmids\": [\"33647291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets (as determined by ChIP-seq), resulting in transactivation of these targets and significant enhancement of cell proliferation in iPSC-derived MSCs. HEY1-NCOA2 (but not wild-type HEY1 or NCOA2 alone) directly targets and upregulates PDGFB and PDGFRA, dramatically increasing phospho-AKT (Ser473).\",\n      \"method\": \"ChIP-seq, RNA-seq, iPSC-derived MSC model with inducible expression, Western blot (phospho-AKT)\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genome-wide ChIP-seq and RNA-seq with mechanistic validation (AKT phosphorylation); fusion-specific effects confirmed against WT controls\",\n      \"pmids\": [\"35342947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ETV6-NCOA2 forms a transcriptional complex with ETV6 and histone acetyltransferase p300, leading to derepression of ETV6 target genes. Expression in nonthymic hematopoietic progenitors (mouse BM and human CD34+ cord blood) induces T/myeloid leukemia by activating a lymphoid program while failing to repress myeloid genes (CSF1, MEF2C); co-acquisition of activating NOTCH1 mutations is required for full leukemic transformation.\",\n      \"method\": \"Co-immunoprecipitation (ETV6-NCOA2/ETV6/p300 complex), ChIP, mouse BM transduction/transplantation model, human cord blood xenograft model, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP establishing complex, ChIP, and two independent in vivo leukemia models (mouse and human); multiple orthogonal methods with mechanistic insight\",\n      \"pmids\": [\"34624096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ncoa2 promotes CD8+ T cell activation and antitumor immunity by upregulating PGC-1α expression to enhance mitochondrial biogenesis and function. T-cell activation-induced CREB phosphorylation triggers Ncoa2 recruitment to PGC-1α enhancers. T cell-specific Ncoa2 knockout (Ncoa2fl/fl/CD4Cre) causes defective mitochondrial mass increase, impaired oxidative phosphorylation, reduced IFNγ, and failure to reject tumors. Forced PGC-1α expression rescues these defects.\",\n      \"method\": \"Conditional T cell-specific KO mice, ChIP (CREB-induced Ncoa2 enhancer recruitment), mitochondrial functional assays, adoptive transfer tumor rejection, PGC-1α rescue experiment\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP, mitochondrial function assays, adoptive transfer, and genetic rescue; multiple orthogonal methods establishing mechanistic pathway\",\n      \"pmids\": [\"37540802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HEY1-NCOA2 expression in mouse embryonic superficial zone cells induces mesenchymal chondrosarcoma with biphasic morphology. HEY1-NCOA2 interacts with Runx2 (via NCOA2 C-terminal domains) and enhances chondrocyte differentiation gene programs; ChIP-seq shows frequent interaction between HEY1-NCOA2 binding peaks and active enhancers. Runx2 knockout delays tumor onset but induces aggressive small round cell growth. HDAC inhibitor panobinostat suppresses tumor growth by abrogating HEY1-NCOA2/Runx2 downstream gene expression.\",\n      \"method\": \"Mouse tumor model, ChIP-seq, co-immunoprecipitation (HEY1-NCOA2/Runx2), HDAC inhibitor treatment, gene expression analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse tumor model, co-IP, ChIP-seq, genetic epistasis (Runx2 KO), and pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"37212282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein itself are necessary for indefinite proliferation of MOZ-TIF2 AML cells; pharmacological inhibition or targeted protein degradation of KAT6 activity abolishes this. MOZ-TIF2 directly regulates a small subset of developmental transcription factor genes, and transcription levels correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr).\",\n      \"method\": \"Pharmacological KAT6 inhibition, targeted protein degradation (PROTAC), histone modification profiling (H3K23pr), ChIP, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic inhibition combined with targeted degradation, ChIP, and histone modification analysis; multiple mechanistic approaches in single study\",\n      \"pmids\": [\"38889153\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA2 (TIF2/SRC-2) is a p160 family transcriptional coactivator that binds liganded nuclear receptor ligand-binding domains via three LxxLL NR-box motifs in its receptor interaction domain; its AD1 region recruits CBP/p300 while AD2 acts independently, and it can also directly bind and structurally reorganize the intrinsically disordered AF1 domain of steroid receptors. Beyond nuclear receptor coactivation, NCOA2 serves as a coactivator for BMAL1:CLOCK circadian oscillators, SREBP-1, and RORα in metabolic gene regulation; it is phosphorylated by mTORC1 and PFKFB4 to modulate its transcriptional activity; in CD8+ T cells it is recruited to the PGC-1α enhancer by CREB to support mitochondrial biogenesis and antitumor immunity; and recurrent fusion with MOZ creates an oncogenic complex that requires both MOZ nucleosomal targeting and TIF2-mediated CBP recruitment (via AD1) to transform hematopoietic progenitors into leukemic stem cells, while fusions with HEY1 (in mesenchymal chondrosarcoma), ETV6, PAX3, SRF, TEAD1, AHRR, VGLL2, and MEIS1 drive distinct sarcoma and leukemia subtypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCOA2 (TIF2/SRC-2/GRIP1) is a p160-family transcriptional coactivator that couples liganded nuclear receptors to the general transcription machinery and chromatin-modifying enzymes [#0, #1]. It engages agonist-bound receptor ligand-binding domains through three LxxLL NR-box motifs in an intrinsically disordered receptor-interaction domain that becomes structured upon receptor engagement, with flanking sequences contributing to a multisite binding mode [#1, #44]; its AD1 region transactivates by recruiting CBP/p300 while AD2 acts independently [#1]. Beyond classical LBD binding, NCOA2 directly binds and increases the α-helical content of the disordered AF1 domain of steroid receptors, and can bridge receptor AF1 and AF2 surfaces to produce synergistic activation [#6, #27]. Context determines its output: NCOA2 also acts as a corepressor at glucocorticoid-repressed genes [#8], and integrates upstream signaling through PKA-dependent destabilization [#9], mTORC1-dependent phosphorylation [#32], and PFKFB4-mediated Ser487 phosphorylation [#43]. Knockout mice establish non-redundant physiological roles in reproduction [#11], adaptive thermogenesis and obesity resistance [#12, #25], and hepatic glucose homeostasis, where NCOA2 coactivates RORα to control glucose-6-phosphatase and prevents a Von Gierke-like glycogenopathy [#21]. NCOA2 further serves as a coactivator of the BMAL1:CLOCK circadian oscillator [#34] and of SREBP-1 in lipogenesis [#32, #36], and supports CD8+ T-cell antitumor immunity by CREB-directed recruitment to the PGC-1α enhancer to drive mitochondrial biogenesis [#47]. In cancer, NCOA2 behaves as both a tumor suppressor (cooperating against MYC-driven liver tumorigenesis) [#29, #39] and an oncogenic driver, most notably as a recurrent fusion partner: the MOZ-TIF2 fusion transforms hematopoietic progenitors by combining MOZ nucleosomal targeting and HAT activity with TIF2/AD1-mediated CBP recruitment [#4, #13, #31], and fusions with HEY1, ETV6, and PAX3 drive mesenchymal chondrosarcoma, leukemia, and rhabdomyosarcoma respectively [#45, #46, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established NCOA2 as a bona fide nuclear receptor coactivator, defining the core activity from which all later functions derive — that it binds agonist-bound receptor LBDs and autonomously activates transcription.\",\n      \"evidence\": \"Cloning with yeast two-hybrid, in vitro LBD binding, and mammalian reporter assays\",\n      \"pmids\": [\"8670870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the binding motifs or the activation domains\", \"No endogenous target genes identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved the molecular grammar of receptor engagement and transactivation by mapping three LxxLL NR-boxes for receptor binding and separating AD1 (CBP-dependent) from AD2 (CBP-independent) activation surfaces.\",\n      \"evidence\": \"Systematic NR-box mutagenesis, two-hybrid, reporter and dominant-negative peptide assays across two studies\",\n      \"pmids\": [\"9430642\", \"9742117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NR-box selectivity not resolved\", \"How AD2 activates transcription mechanistically unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Connected coactivator recruitment to receptor surface integrity and identified the oncogenic MOZ-TIF2 fusion, framing both physiological AF-2 dependence and a disease-relevant rearrangement.\",\n      \"evidence\": \"AR AF-2 residue mutagenesis (E888) plus FISH/RT-PCR characterization of inv(8) fusion\",\n      \"pmids\": [\"9717843\", \"9558366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fusion oncogenicity not functionally tested at this stage\", \"AF-2 contact mode inferred from mutants only\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed NCOA2 bridges receptor AF1 and AF2 domains to drive synergy, extending its action beyond LBD docking and revealing isotype-selective, p160-non-redundant bridging.\",\n      \"evidence\": \"Mammalian two-hybrid, in vitro binding, and domain-selective mutants on ERα and RARα1\",\n      \"pmids\": [\"11265755\", \"12149266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of dual-domain bridging unresolved\", \"Generality across receptors untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated NCOA2 can act as a corepressor at specific glucocorticoid-repressed genes, establishing that its transcriptional output is context-dependent rather than uniformly activating.\",\n      \"evidence\": \"ChIP, reporter and dominant-negative mutant analysis at the col3A response element\",\n      \"pmids\": [\"11689447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repression mechanism / partner enzymes not defined\", \"Promoter determinants of activator-vs-repressor switch unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined upstream signal control and the first physiological roles, showing PKA destabilizes NCOA2 via AD2 and that loss in mice produces distinct reproductive and metabolic phenotypes.\",\n      \"evidence\": \"PKA cotransfection with domain deletions; TIF2-null mouse reproductive and metabolic phenotyping with co-IP of SRC-1/PGC-1α\",\n      \"pmids\": [\"11923473\", \"12138202\", \"12507421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKA does not phosphorylate a defined NCOA2 residue here\", \"Tissue-specific target genes not fully resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Proved MOZ-TIF2 is leukemogenic in vivo and dissected the required modules — MOZ nucleosome recognition plus TIF2/AD1-mediated CBP recruitment — converting an associative fusion into a mechanistic oncogene.\",\n      \"evidence\": \"Murine bone marrow transplant AML model with systematic domain-deletion mutants; β-catenin/AR/TIF2 three-way complex by co-IP and two-hybrid\",\n      \"pmids\": [\"12676584\", \"12588987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes of MOZ-TIF2 not yet identified at this stage\", \"MOZ HAT role appeared dispensable here but revisited later\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established p160 functional redundancy and a nuclear-compartment model, showing SRC-1 compensates in Sertoli cells and that TIF2 forms pre-assembled foci that recruit GR and coactivators upon ligand.\",\n      \"evidence\": \"SRC-1/TIF2 compound-mutant mice; immunofluorescence/live imaging with microinjected GRE\",\n      \"pmids\": [\"15070739\", \"15207724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of foci formation undefined\", \"Degree of redundancy across other tissues unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Clarified the dominant-negative mechanism of MOZ-TIF2 and a β-catenin bridging route, showing the fusion sequesters CBP via AD1 and depletes it from PML bodies.\",\n      \"evidence\": \"Reciprocal co-IP, FRET, immunofluorescence and reporter assays; β-catenin/TIF2/AR co-IP and dominant-negative peptide\",\n      \"pmids\": [\"15657427\", \"16141201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CBP sequestration translates to specific gene deregulation unresolved\", \"β-catenin bridging significance in vivo untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified accessory regulators and a corepressor-competition mechanism, showing an N-terminal NCOA2 fragment competes with NCoR/SMRT for receptor binding and that STAMP/TTLL5 modulates NCOA2 output.\",\n      \"evidence\": \"Two-hybrid, pulldown, co-IP, ChIP, siRNA of endogenous STAMP, NCoR mutagenesis (two studies)\",\n      \"pmids\": [\"17116691\", \"17571860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of NCoR competition at endogenous genes limited\", \"STAMP/TTLL5 enzymatic contribution to NCOA2 regulation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a discrete metabolic function in hepatic glucose release, linking NCOA2 to RORα coactivation of G6Pase and revealing a glycogenopathy phenotype on its loss.\",\n      \"evidence\": \"Whole-body and liver-specific knockout mice with metabolic phenotyping, RORα coactivation and ChIP\",\n      \"pmids\": [\"19039140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full hepatic complex composition not yet mapped\", \"Signal that activates NCOA2 during fasting undefined here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the muscle/metabolism axis and the leukemia mechanism, showing TIF2 antagonizes SRC-1/UCP3 in muscle and that MOZ-TIF2 requires PU.1 to drive CSF1R for leukemia stem-cell maintenance.\",\n      \"evidence\": \"Inducible muscle-specific knockout with metabolic phenotyping; co-IP, PU.1-deficient mice, CSF1R inhibitor, serial transplantation\",\n      \"pmids\": [\"21035760\", \"20418886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SRC-1/TIF2 antagonism at UCP3 not fully defined\", \"How PU.1 cooperates structurally with the fusion unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined NCOA2's role in adipogenesis and the biophysics of AF1 engagement, showing it can directly fold the disordered GR AF1 and that it suppresses inhibitory PPARγ-S114 phosphorylation; also revealed a tumor-suppressor role in liver.\",\n      \"evidence\": \"siRNA single-cell adipocyte assays; CD and HDX-MS on GR AF1; cardiac and Sleeping Beauty/MYC liver tumor models\",\n      \"pmids\": [\"21220509\", \"23132854\", \"23300926\", \"22556267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the NCOA2-AF1 complex not at residue resolution\", \"Tumor-suppressor target genes not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Refined MOZ-TIF2 leukemogenesis to require MOZ HAT activity via a BRPF1-containing complex at HOX genes, and identified PAX3-NCOA2 as a rhabdomyosarcoma driver.\",\n      \"evidence\": \"Co-IP, ChIP, shRNA, HAT-mutant fusion and AML model; PAX3-NCOA2 cell-line and xenograft assays\",\n      \"pmids\": [\"24258712\", \"24213582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with earlier HAT-dispensable finding context-dependent\", \"PAX3-NCOA2 endogenous target genes not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established NCOA2 as a circadian and oncogenic metabolic hub, coactivating BMAL1:CLOCK genome-wide and, downstream of mTORC1, SREBP-1 to drive glutamine-fueled lipogenesis and prostate cancer.\",\n      \"evidence\": \"ChIP-seq with KO behavioral/metabolomic phenotyping; isotope tracing, co-IP, xenografts and prostate GOF/LOF mouse models\",\n      \"pmids\": [\"24529706\", \"25664849\", \"25295534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mTORC1-phosphorylated NCOA2 residue not pinpointed here\", \"Crosstalk between circadian and lipogenic programs unexplored\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded NCOA2's regulatory range to Wnt/β-catenin suppression, SREBP-1-driven lipid/glucose genes (metformin target), and HIF-1α/AhR competition controlling angiogenesis.\",\n      \"evidence\": \"GOF/LOF reporter, ChIP and xenograft assays across colorectal, hepatic and angiogenesis models\",\n      \"pmids\": [\"25823027\", \"26548416\", \"26350169\", \"26487680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect pathway effects not always separated\", \"Mechanism of ARNT-competition not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the direct anti-tumorigenic target genes (SHP, DKK4, CADM4) through which NCOA2 suppresses MYC-driven liver cancer, giving molecular substance to its tumor-suppressor role.\",\n      \"evidence\": \"In vivo ChIP-seq, RNA-seq, KO tumor model and functional rescue with individual target genes\",\n      \"pmids\": [\"28273073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/partner directing NCOA2 to these promoters not defined\", \"Why the same coactivator is oncogenic elsewhere unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the decidualization transcriptome and refined leukemic fusion mechanism, showing NCOA2 is required for full PGR response in endometrium and that ETV6-NCOA2 recruits p300 to derepress ETV6 targets.\",\n      \"evidence\": \"ChIP-seq/RNA-seq with siRNA in primary hESCs; co-IP, ChIP and mouse/human leukemia models; Ring1A/B-Glis2 epistasis in AML\",\n      \"pmids\": [\"30325183\", \"34624096\", \"29371181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NOTCH1 cooperativity mechanism with ETV6-NCOA2 incomplete\", \"PRC1 link to NCOA2-fusion chromatin state indirect\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-transcriptional, virology role: NCOA2 stabilizes the KSHV RTA protein by competing with MDM2, promoting lytic reactivation through a positive feedback loop.\",\n      \"evidence\": \"In vitro and in vivo co-IP, MDM2 competition and proteasome assays, GOF/LOF in infected cells\",\n      \"pmids\": [\"31751430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NCOA2 stabilizes other clients similarly unknown\", \"Structural basis of PARS II binding not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Pinpointed signaling control and the disordered structural basis of receptor recognition, identifying PFKFB4-mediated Ser487 phosphorylation and resolving the multisite NR-box binding mode by NMR/crystallography.\",\n      \"evidence\": \"Co-IP, phospho-Ser487 immunoblot and functional assays; NMR, SAXS, X-ray and SEC-MALS of TIF2NRID with RXR/RAR\",\n      \"pmids\": [\"33593309\", \"33647291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of disorder-to-order transition in cells untested\", \"How distinct phosphorylations integrate combinatorially unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically resolved the HEY1-NCOA2 chondrosarcoma fusion, showing it occupies canonical HEY1 promoters and upregulates PDGFB/PDGFRA to activate AKT signaling.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, inducible iPSC-derived MSC model and phospho-AKT immunoblot\",\n      \"pmids\": [\"35342947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NCOA2 moiety's coactivator contribution to fusion activity not isolated\", \"Therapeutic targetability of the PDGF axis untested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined NCOA2's role in immunometabolism and chondrosarcoma in vivo, showing CREB-directed recruitment to the PGC-1α enhancer drives CD8+ T-cell mitochondrial biogenesis and that HEY1-NCOA2 cooperates with Runx2, an HDAC-inhibitor-sensitive program.\",\n      \"evidence\": \"T-cell conditional KO with ChIP, mitochondrial assays, adoptive transfer and PGC-1α rescue; mouse chondrosarcoma model with co-IP, ChIP-seq, Runx2 KO and panobinostat\",\n      \"pmids\": [\"37540802\", \"37212282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear receptor partner in the T-cell PGC-1α axis not identified\", \"Runx2-independent fusion programs incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed KAT6 enzymatic dependence of MOZ-TIF2 AML and linked the fusion to histone H3K23 propionylation at a small set of developmental transcription factor genes, defining a druggable enzymatic node.\",\n      \"evidence\": \"Pharmacological KAT6 inhibition and PROTAC degradation, H3K23pr profiling, ChIP and gene expression analysis\",\n      \"pmids\": [\"38889153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of H3K23pr versus acetylation not separated\", \"Which target genes are the essential drivers undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single coactivator integrates its many phosphorylation inputs (PKA, mTORC1, PFKFB4) and partner contexts to switch between activator, corepressor, tumor-suppressor and oncogenic-fusion behaviors at specific loci.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking post-translational state to genomic target selection\", \"Structural basis of context-dependent activator/repressor switching unknown\", \"Endogenous full coactivator complex composition across tissues incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 21, 34, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 8, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 13, 46]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 21, 25, 32]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 13, 30, 45, 46]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 32, 43, 47]}\n    ],\n    \"complexes\": [\n      \"MOZ-TIF2/BRPF1 complex\",\n      \"BMAL1:CLOCK coactivator complex\",\n      \"ETV6-NCOA2/p300 complex\"\n    ],\n    \"partners\": [\n      \"CREBBP\",\n      \"EP300\",\n      \"CTNNB1\",\n      \"AR\",\n      \"ESR1\",\n      \"BMAL1\",\n      \"SREBF1\",\n      \"TTLL5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}