{"gene":"NCOA2","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1996,"finding":"TIF2 (NCOA2) was cloned as a 160 kDa nuclear protein that interacts with nuclear receptors (NRs) in vivo in an agonist-dependent manner, binds directly to the ligand-binding domains (LBDs) of NRs 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, establishing it as a bona fide coactivator of NR AF-2.","method":"Co-immunoprecipitation, GST pulldown, yeast two-hybrid, mammalian cell transfection reporter assays, squelching assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in a foundational paper; 904 citations indicating broad replication","pmids":["8670870"],"is_preprint":false},{"year":1996,"finding":"GRIP1 (mouse ortholog of NCOA2/TIF2) interacts with the hormone-binding domains (HBDs) of glucocorticoid, estrogen, and androgen receptors in a hormone-regulated manner in yeast two-hybrid and in vitro assays, and contains a transcriptional activation domain; overexpression squelches hormone-regulated and constitutive (CMV) reporter gene expression but not tRNA-driven expression, indicating interaction with the RNA Pol II machinery.","method":"Yeast two-hybrid, in vitro binding, mammalian reporter squelching assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, foundational paper with 598 citations","pmids":["8643509"],"is_preprint":false},{"year":1997,"finding":"Full-length GRIP1/NCOA2 interacts in a hormone-dependent manner with all five steroid receptors and class II nuclear receptors (TRα, VDR, RARα, RXRα) via their hormone-binding domains; it serves as a transcriptional coactivator in yeast for all tested receptors but enhances only a subset in mammalian cells; experiments with GR truncation and point mutants demonstrate that GRIP1 interacts with and enhances specifically the C-terminal AF-2 but not the N-terminal AF-1 transactivation domain of GR.","method":"Yeast two-hybrid, in vitro binding, mammalian reporter assays, GR truncation/point mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus multiple receptor systems, 482 citations","pmids":["9111344"],"is_preprint":false},{"year":1997,"finding":"The rat homolog of TIF2 (NCOA2) contains three short conserved NR box motifs (LXXLL) in its receptor interaction domain (NID); all three NR boxes are necessary and sufficient for interaction with nuclear hormone receptors, individual boxes display preference for certain receptors, and cooperative binding of two TIF2 molecules to a heterodimeric NR complex occurs even with only one cognate ligand, revealing an allosteric effect on the heterodimeric partner.","method":"Yeast two-hybrid, mutagenesis of NR boxes, GST pulldown, mammalian two-hybrid","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of defined motifs combined with binding assays","pmids":["9742117"],"is_preprint":false},{"year":1998,"finding":"TIF2 (NCOA2) possesses a single NR interaction domain (NID) composed of three NR-interacting modules each containing the LxxLL (NR box) motif; the AD1 activation domain activity is mediated through CBP (and could not be separated mutationally from the CBP interaction domain), while AD2 activity does not involve CBP. An NID peptide acting as dominant-negative blocked AF-2 of several NRs in mammalian cells, confirming that endogenous TIF2 mediates NR AF-2 activity.","method":"Mutagenesis, mammalian and yeast transfection assays, dominant-negative peptide competition","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — mutational dissection of functional domains, replicated across systems; 430 citations","pmids":["9430642"],"is_preprint":false},{"year":1998,"finding":"A novel chromosomal inversion inv(8)(p11q13) in acute myeloid leukemia fuses MOZ (a MYST-family histone acetyltransferase) to TIF2/NCOA2, producing a chimeric protein that retains MOZ HAT homology domains and the CBP-binding domain and activation domains of TIF2, implicating aberrant histone acetylation and CBP recruitment as potential leukemogenic mechanisms.","method":"FISH, Southern blot, RT-PCR, sequence analysis of fusion breakpoints","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning of fusion with domain analysis, single lab","pmids":["9558366"],"is_preprint":false},{"year":1998,"finding":"SRC-1 and GRIP1 (NCOA2) associate with HNF4 in vivo (co-immunoprecipitation) and enhance its transactivation; the AF-2 domain of HNF4 is required for this interaction and for transcriptional potentiation; p300 synergizes with SRC-1 to further augment HNF4 activity; overexpression of SRC-1 or GRIP1 enhances expression from the HNF1 gene promoter in an HNF4-binding-site-dependent manner.","method":"Co-immunoprecipitation, mammalian reporter assays, promoter mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo co-IP plus functional reporter assays","pmids":["9812974"],"is_preprint":false},{"year":1998,"finding":"GRIP-1 (NCOA2) functions as a coactivator for estrogen receptor (ER) even when AF-2 core sequences are mutated, indicating the HBD of ER contains multiple GRIP1 binding sites or contacts beyond AF-2; AF-2 deletion alters ligand pharmacology such that ER loses discrimination between agonists and antagonists, and on these mutants GRIP1 still coactivates irrespective of bound ligand.","method":"Mammalian reporter assays, ER AF-2 mutagenesis, ligand pharmacology analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with functional readout, single lab","pmids":["9506965"],"is_preprint":false},{"year":1999,"finding":"GRIP1 (NCOA2) coactivation of CARM1 (coactivator-associated arginine methyltransferase 1) was discovered: CARM1 binds to the carboxyl-terminal region of p160 coactivators including GRIP1/TIF2, and enhances NR-mediated transcription only when GRIP1 or SRC-1a is coexpressed; CARM1 methylates histone H3 in vitro and mutation of its SAM-binding domain abolishes both methyltransferase and coactivator activities, establishing CARM1 as a secondary coactivator recruited through GRIP1.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro histone methyltransferase assay, mutagenesis, mammalian reporter assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro methyltransferase + mutagenesis + cell-based assays; 991 citations","pmids":["10381882"],"is_preprint":false},{"year":1999,"finding":"An auxiliary NR interaction domain (NIDaux, aa 1011–1121) in GRIP1 (NCOA2) is required in vitro and in vivo for efficient interaction with a subset of NRs including GR, androgen receptor, and RARα; a second group of NRs (PR, RXRα, TRβ1, VDR) requires only the canonical NID; NID and NIDaux must act in cis for GR binding; the p300 interaction function within NIDaux is separable from its GR-binding contribution by mutagenesis.","method":"In vitro GST pulldown, mammalian two-hybrid, deletion and point mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis dissecting separable functions within a domain","pmids":["9920895"],"is_preprint":false},{"year":1999,"finding":"p160 coactivators including GRIP1 (NCOA2) contain two signal output domains: AD1 (which binds CBP/p300 via a conserved motif) and AD2 (which is CBP/p300-independent); the C-terminal region of GRIP1 also binds the N-terminal AF-1 domain of androgen receptor, showing that GRIP1 has two signal input domains (binding NR AF-2 and AF-1) and two signal output domains (AD1 and AD2) that play different relative roles for different NRs.","method":"Deletion mutagenesis, GST pulldown, mammalian reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — systematic mutagenesis defining domain architecture; 208 citations","pmids":["10454563"],"is_preprint":false},{"year":2000,"finding":"TIF2 (NCOA2) can interact simultaneously with both the isolated N-terminus (AF1) and C-terminus (AF2) of ERα in transfected mammalian cells and in vitro, bridging both receptor domains; this concomitant interaction results in synergistic transcriptional activation, establishing that AF1–AF2 synergy is mediated by cooperative recruitment of TIF2.","method":"Mammalian two-hybrid, in vitro binding, reporter assays with TIF2 mutants deficient in AF1 or AF2 interaction","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of both AF1 and AF2 binding surfaces of TIF2 with functional readouts","pmids":["11265755"],"is_preprint":false},{"year":2001,"finding":"TIF2/GRIP1 (NCOA2) is recruited to the AP-1 site at the collagenase-3 (col3A) response element in human U2OS cells and potentiates GR-mediated transcriptional repression in the presence of GR agonist but not antagonist; GRIP1 mutants deficient in GR binding and coactivator functions are also defective for corepression; a GRIP1 fragment containing the GR-interacting region acts as dominant-negative for repression, revealing a corepressor function for GRIP1 at AP-1 tethering GREs.","method":"Chromatin immunoprecipitation (ChIP), reporter assays, dominant-negative GRIP1 fragments, mutant analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating in vivo recruitment plus functional mutagenesis","pmids":["11689447"],"is_preprint":false},{"year":2002,"finding":"GRIP1 (NCOA2) acts as a GR coactivator at classical GREs and as a GR corepressor at AP-1 (collagenase-3) and NF-κB (IL-8) tethering GREs; the corepressor activity maps to a GRIP1 domain distinct from the two known activation domains (AD1, AD2); this repression domain has intrinsic GR-independent repression activity when recruited to DNA via Gal4-DBD; neither SRC1 nor RAC3 (SRC-3) possess this corepression domain, establishing GRIP1 as unique among p160 coactivators for GR-mediated transrepression.","method":"Domain mapping, Gal4-tethered reporter assays, comparative analysis of p160 family members","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — functional domain mapping with mutagenesis across multiple response elements","pmids":["12481024"],"is_preprint":false},{"year":2002,"finding":"The SRC-2/TIF2 (NCOA2) knockout mouse is protected against obesity and displays enhanced adaptive thermogenesis, whereas SRC-1 knockout mice are prone to obesity. In white adipose tissue, TIF2 loss decreases PPARγ activity and reduces fat accumulation; in brown adipose tissue, TIF2 loss facilitates SRC-1–PGC-1α interaction, which induces PGC-1α thermogenic activity, revealing antagonistic roles of TIF2 and SRC-1 in energy homeostasis.","method":"Genetic knockout mice, PPARγ activity assays, co-immunoprecipitation of SRC-1 and PGC-1α, thermogenesis measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with mechanistic co-IP evidence; 365 citations","pmids":["12507421"],"is_preprint":false},{"year":2002,"finding":"TIF2/GRIP1 (NCOA2) knockout mice are viable but hypofertile in both sexes: male hypofertility results from spermiogenesis defects (teratozoospermia) and age-dependent testicular degeneration, with TIF2 essential for Sertoli cell adhesion to germ cells; female hypofertility results from placental hypoplasia requiring maternal TIF2 in decidua stromal cells, demonstrating distinct in vivo physiological roles from SRC-1 and p/CIP.","method":"Gene knockout (TIF2−/− mice), histological analysis, phenotypic characterization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular and tissue-level phenotypes","pmids":["12138202"],"is_preprint":false},{"year":2002,"finding":"SUMO-1 is covalently attached to GRIP1 (NCOA2) at lysine residues 239, 731, and 788; Lys-731 and Lys-788 in the NR interaction domain (NID) are principal sites, and their substitution by arginine impairs GRIP1's ability to colocalize with androgen receptor in nuclei, attenuates AR-dependent transcription enhancement, and abolishes synergy with PIASxβ-mediated AR activation, establishing sumoylation as a PTM that modulates GRIP1 coactivator function.","method":"Site-directed mutagenesis of SUMO attachment sites, co-immunoprecipitation, confocal microscopy, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of specific SUMO sites with functional and localization readouts","pmids":["12060666"],"is_preprint":false},{"year":2002,"finding":"TIF2 (NCOA2) forms nuclear foci and can recruit GR to these foci upon agonist but not antagonist treatment; secondary coactivators p300 and PCAF are also recruited to TIF2 foci; TIF2 foci can recruit GR carrying a microinjected GR-responsive element, suggesting that TIF2 provides a pre-assembled nuclear compartment for multi-protein complex assembly required for GR-mediated gene activation.","method":"Immunofluorescence, live-cell imaging of nuclear foci, microinjection of GRE, confocal microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence (GRE recruitment)","pmids":["15207724"],"is_preprint":false},{"year":2003,"finding":"MOZ-TIF2 fusion causes AML in a murine bone marrow transplant assay; the C2HC nucleosome recognition motif of MOZ is essential for transformation while MOZ HAT activity is dispensable; the TIF2 CBP-interaction domain (CID/AD1) is essential for transformation, establishing that nucleosomal targeting by MOZ and CBP recruitment by the TIF2 portion are both critical mechanistic requirements for MOZ-TIF2 leukemogenesis.","method":"Murine bone marrow transplantation, domain deletion/mutation analysis, in vitro colony assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo leukemia model with mutational dissection of essential domains","pmids":["12676584"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the human GR ligand-binding domain bound to dexamethasone and a coactivator motif derived from TIF2 (NCOA2) reveals the structural basis of LxxLL-motif recognition, an additional charge clamp determining coactivator binding selectivity, and a novel GR dimerization interface involving an intermolecular β-sheet.","method":"X-ray crystallography of GR LBD:TIF2 peptide complex, functional validation of dimer interface mutations","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation; 670 citations","pmids":["12151000"],"is_preprint":false},{"year":2004,"finding":"GRIP1 (NCOA2) is ubiquitinated and degraded via the ubiquitin-proteasome pathway upon activation of cAMP-dependent protein kinase (PKA); PKA increases GRIP1 turnover (shown by pulse-chase), GRIP1 ubiquitination is increased by PKA overexpression (shown by co-immunoprecipitation with ubiquitin antibody), proteasome inhibitors block PKA-mediated degradation, and PKA stimulates recruitment of GRIP1 to subnuclear foci co-localizing with the proteasome.","method":"Pulse-chase, co-immunoprecipitation with ubiquitin, proteasome inhibitors (MG132, lactacystin), temperature-sensitive E1 mutant cells, GFP-GRIP1 live imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including ts20 E1-deficient cells and live imaging","pmids":["15347661"],"is_preprint":false},{"year":2005,"finding":"GRIP1 (NCOA2) acts as a GR corepressor at the IRF3-responsive pathway: a yeast two-hybrid screen with the GRIP1 corepression domain identified IRF3 as a binding partner; endogenous GRIP1 and IRF3 interact in macrophages (co-immunoprecipitation); GR and IRF3 compete for GRIP1 binding; GR activation or GRIP1 knockdown blocks IRF3-dependent gene expression, while GRIP1 overexpression rescues it, establishing GRIP1 as a cofactor in innate immunity whose sequestration by GR suppresses TLR3-IRF3 signaling.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, macrophage reporter assays, IRF3-deficient and MyD88-deficient mice","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic knockdown/overexpression, in vivo mouse models","pmids":["16362036"],"is_preprint":false},{"year":2005,"finding":"GRIP1 (NCOA2) mediates the androgen receptor (AR) N-terminal/C-terminal (N/C) interaction: wild-type GRIP1 bridges AR-NTD and AR-LBD; co-expression of mutant GRIP1 lacking either AR interaction domain fails to restore N/C interaction; mutation of the AR-NTD FQNLF motif abolishing N/C interaction is rescued by GRIP1 coexpression, indicating that GRIP1 normally bridges the two AR domains to stabilize the N/C complex and facilitate secondary cofactor recruitment.","method":"Mammalian two-hybrid, AR N/C interaction assays, point mutagenesis of GRIP1 interaction domains","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue experiments with defined mutants","pmids":["15843149"],"is_preprint":false},{"year":2005,"finding":"MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent activators (nuclear receptors, p53) by directly interacting with CBP in vivo (co-immunoprecipitation and FRET); the CBP-binding domain (AD1) of the TIF2 portion is required for this dominant-negative effect and for extending proliferative potential of murine bone marrow cells; MOZ-TIF2 displays aberrant nuclear distribution and reduces cellular CBP levels, depleting CBP from PML bodies.","method":"Co-immunoprecipitation, FRET, reporter assays, bone marrow progenitor proliferation assays, immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — FRET + Co-IP demonstrating direct in vivo interaction, functional domain requirement","pmids":["15657427"],"is_preprint":false},{"year":2005,"finding":"β-catenin interacts directly with TIF2/GRIP1 (NCOA2) and with AR in a three-way complex; both N- and C-terminal regions of β-catenin are needed for optimal TIF2 interaction; β-catenin and TIF2 each mediate binding between the other and AR; a β-catenin C-terminal peptide binds TIF2 and AR but acts as a dominant inhibitor of ligand-dependent transcription, suggesting that AR–β-catenin–TIF2 form a ternary transcriptional complex.","method":"Co-immunoprecipitation, GST pulldown, point mutagenesis, mammalian reporter assays, dominant-negative peptide analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple binding assays with mutagenesis, single lab","pmids":["16141201"],"is_preprint":false},{"year":2005,"finding":"Among p160 coactivators, GRIP1 (NCOA2) uniquely acts as a corepressor (not coactivator) of MyoD-mediated transcription; SRC1A and p/CIP coactivate via distinct sites on MyoD's N-terminal activation domain, whereas GRIP1 binds both these regions and additionally interacts with MyoD sites critical for p300 binding, suggesting GRIP1 competes with p300 for MyoD interaction and thereby suppresses MyoD activity.","method":"Reporter assays, GST pulldown with MyoD deletion/point mutants, domain competition analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter plus binding domain mapping, single lab","pmids":["15563453"],"is_preprint":false},{"year":2005,"finding":"GAC63, a novel coactivator, binds to the N-terminal region of GRIP1 (NCOA2) and the LBDs of some NRs; GAC63 enhances NR transcriptional activation in a hormone-dependent and GRIP1-dependent manner; endogenous GAC63 is recruited to the estrogen-responsive pS2 gene promoter in MCF-7 cells; siRNA knockdown of GAC63 inhibits ER-activated transcription, establishing GAC63 as a physiologically relevant component of the GRIP1-containing p160 coactivator complex.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, ChIP, siRNA knockdown, reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus siRNA with functional readout","pmids":["15988012"],"is_preprint":false},{"year":2006,"finding":"STAMP, a 1,277-aa protein, associates with TIF2 (NCOA2) and SRC-1 but is selective for a subset of receptors including GR; transfected STAMP increases TIF2 effects in GR-mediated repression and induction; siRNA knockdown of endogenous STAMP reduces both induction and repression of endogenous GR target genes; endogenous STAMP co-localizes with GR in intact cells and is recruited to promoters of GR-induced and -repressed genes by ChIP, establishing STAMP as a downstream cofactor of TIF2 in GR action.","method":"Co-immunoprecipitation, siRNA knockdown, ChIP, reporter assays, immunofluorescence co-localization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and siRNA with endogenous gene readouts","pmids":["17116691"],"is_preprint":false},{"year":2007,"finding":"GRIP1 (NCOA2) directly interacts with RIP140 through its carboxyl-terminal AD2 domain and serves as a platform molecule at the TR2 promoter; retinoic acid triggers exchange of PCAF (histone acetyltransferase) for RIP140 (histone deacetylase) on the GRIP1/TR2 complex, converting the locus from activation to repression and mediating the biphasic effect of RA on TR2 expression in preadipocytes versus adipocytes.","method":"Co-immunoprecipitation, ChIP, reporter assays, domain mapping of GRIP1–RIP140 interaction","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP showing coregulator exchange on promoter, Co-IP for direct interaction","pmids":["17389641"],"is_preprint":false},{"year":2007,"finding":"An N-terminal fragment of TIF2 (TIF2.0, aa 1–627) competes with corepressors NCoR and SMRT for binding to GR and PR in mammalian two-hybrid and pull-down assays; NCoR RID#1 (but not RID#2) is necessary for binding to GR and PR; ChIP shows that exogenous TIF2.0 reduces NCoR occupancy at a PRE in the presence of antagonist; these results show that N-terminal TIF2 sequences (distinct from the canonical NID) compete with corepressors for receptor binding and oppose corepressor-mediated biological responses.","method":"Mammalian two-hybrid, pull-down, co-immunoprecipitation, ChIP, reporter assays, NCoR mutagenesis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus biochemical assays, single lab","pmids":["17571860"],"is_preprint":false},{"year":2008,"finding":"SRC-2 (NCOA2) regulates fasting hepatic glucose release by controlling expression of glucose-6-phosphatase (G6Pase); SRC-2 directly coactivates the orphan nuclear receptor RORα to drive G6Pase expression; whole-body and liver-specific SRC-2 ablation in mice produces a Von Gierke's disease (glycogen storage disease-1a) phenotype with hepatic glycogen accumulation, positioning SRC-2 as a critical regulator of hepatic glucose production.","method":"Whole-body and conditional (liver-specific) knockout mice, reporter assays showing RORα coactivation, glucose metabolism phenotyping","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with mechanistic coactivation assay and disease phenotype; 136 citations","pmids":["19039140"],"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-deficient mice showed that PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells; CSF1R-high cells (but not CSF1R-low cells) possess leukemia-initiating activity; CSF1R inhibitors slowed MOZ-TIF2-induced leukemia progression.","method":"Co-immunoprecipitation of MOZ-TIF2 with PU.1, PU.1-knockout mouse model, conditional CSF1R-suicide transgene mouse, CSF1R inhibitor treatment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus in vivo genetic epistasis models defining mechanism","pmids":["20418886"],"is_preprint":false},{"year":2010,"finding":"SRC-1 and TIF2 (NCOA2) antagonistically regulate uncoupling protein 3 (UCP3) expression in skeletal muscle myofibers; selective ablation of TIF2 in adult skeletal muscle (TIF2(i)skm−/− mice) increases mitochondrial uncoupling, increases SRC-1 levels, and protects from sedentary-induced loss of oxidative capacity, diet-induced obesity, and type-2 diabetes onset.","method":"Inducible, muscle-specific TIF2 conditional knockout (Cre-lox), mitochondrial respiration measurements, expression analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with defined metabolic phenotype","pmids":["21035760"],"is_preprint":false},{"year":2011,"finding":"A Sleeping Beauty transposon mutagenesis screen in MYC-driven liver cancer identified Ncoa2/Src-2 as a tumor suppressor; RNAi-mediated knockdown of Ncoa2 in liver progenitor cells accelerated tumorigenesis, and deletion of Ncoa2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis, establishing a tumor suppressor role for NCOA2 in liver cancer.","method":"Sleeping Beauty forward genetic screen in mice, RNAi knockdown in liver progenitor cells, chemical carcinogenesis (DEN) in Ncoa2-knockout mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic models (KO + chemical carcinogenesis) with functional validation","pmids":["22556267"],"is_preprint":false},{"year":2011,"finding":"The HEY1-NCOA2 fusion, in which HEY1 exon 4 is fused in-frame to NCOA2 exon 13, is a recurrent gene fusion identified in mesenchymal chondrosarcoma; it was detected in all tested mesenchymal chondrosarcomas with definitive diagnosis but absent in other chondrosarcoma subtypes, establishing it as the defining molecular lesion of this tumor type.","method":"5' RACE, RT-PCR, FISH, Affymetrix Exon array-based fusion score analysis","journal":"Genes, chromosomes & cancer","confidence":"High","confidence_rationale":"Tier 2 — multiple molecular methods confirming recurrent fusion across multiple tumor samples","pmids":["22034177"],"is_preprint":false},{"year":2012,"finding":"Endogenous GRIP1 (NCOA2) undergoes glucocorticoid-induced, GR-interaction-dependent phosphorylation in mammalian cells; one constitutive and six inducible phosphorylation sites were identified, with casein kinase 2 and CDK9 as putative kinases; phosphospecific antibodies combined with mutagenesis demonstrated that phosphorylation at a cluster of closely spaced sites in an uncharacterized GRIP1 region is functionally relevant to GR-activated transcription and to GRE-specific recruitment of phospho-GRIP1 to native GR target genes.","method":"Mass spectrometry phosphoproteomics, phosphospecific antibody generation, site-directed mutagenesis, ChIP at endogenous GR targets","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — MS identification of sites + mutagenesis + ChIP at endogenous loci","pmids":["22158970"],"is_preprint":false},{"year":2012,"finding":"Binding of the N-terminal region of TIF2 (TIF2.0) to the intrinsically disordered AF1 domain of GR is accompanied by an increase in α-helical structure in the complex (shown by biophysical analysis); TIF2 coactivator activity is observed in the absence of GR LBD in an AF1-dependent manner, demonstrating that TIF2 can directly bind and structurally reorganize GR AF1 to promote transcriptional activation independently of the classical LBD–NID interaction.","method":"Hydrogen-deuterium exchange mass spectrometry, circular dichroism, mammalian reporter assays with GR truncations","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — biophysical structural evidence of induced folding, single lab","pmids":["23132854"],"is_preprint":false},{"year":2012,"finding":"Conditional hematopoietic-cell-restricted deletion of GRIP1 (NCOA2) in adult mice demonstrates that GRIP1 is required in macrophages for GR-mediated repression of NF-κB target genes; genome-wide transcriptome analysis reveals broad derepression of LPS-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages; GRIP1-deficient mice are sensitized to LPS-induced shock, establishing that GRIP1 is essential for glucocorticoid anti-inflammatory actions in vivo.","method":"Conditional knockout (Cre-lox restricted to hematopoietic cells), genome-wide RNA-seq, LPS shock model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with genome-wide readout and in vivo inflammatory model","pmids":["22753499"],"is_preprint":false},{"year":2013,"finding":"PAX3-NCOA2 fusion gene promotes proliferation (faster growth, greater motility, anchorage independence, accelerated G1/S, greater PAX3-binding-site transcriptional activation) and inhibits myogenic differentiation of rhabdomyosarcoma cells compared to controls; in stable mouse myoblast C2C12 cells expressing PAX3-NCOA2, both tumorigenic properties are demonstrated in nude mouse xenografts.","method":"Stable cell line generation, proliferation/motility/anchorage assays, cell cycle analysis, luciferase reporter assays, nude mouse xenografts, differentiation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotypes with in vivo validation, single lab","pmids":["24213582"],"is_preprint":false},{"year":2013,"finding":"MOZ-TIF2 forms a stable complex with BRPF1 (bromodomain-PHD finger protein 1) shown by immunoprecipitation; ChIP shows MOZ-TIF2 and BRPF1 interact with HOX gene loci in AML cells; BRPF1 depletion decreases MOZ localization on HOX genes and abrogates MOZ-TIF2 transformation ability; mutant MOZ-TIF2 lacking HAT activity cannot deregulate HOX genes or initiate leukemia, establishing that MOZ-TIF2/BRPF1 upregulates HOX genes via MOZ HAT-mediated histone acetylation.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, HAT-activity mutant, in vitro transformation assays","journal":"International journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + Co-IP + functional mutagenesis, single lab","pmids":["24258712"],"is_preprint":false},{"year":2014,"finding":"NCoA2/SRC-2 (NCOA2) overexpression in mouse prostate epithelium causes neoplasia and, combined with PTEN deletion, promotes metastasis-prone cancer; NCoA2 overexpression leads to hyperactivation of PI3K/AKT and MAPK signaling in murine prostate tumors; androgen signaling suppresses NCoA2 expression in human androgen-sensitive prostate cancer cells; NCoA2 depletion in PTEN-deficient mice prevents development of castration-resistant prostate cancer.","method":"Prostate-specific overexpression mouse model, PTEN-knockout combination, NCoA2 depletion in vivo, PI3K/AKT/MAPK signaling assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo genetic models with defined signaling pathway readouts","pmids":["25295534"],"is_preprint":false},{"year":2014,"finding":"SRC-2 (NCOA2) is an essential coactivator for BMAL1:CLOCK circadian transcription; genome-wide ChIP-seq shows diurnal SRC-2 recruitment extensively overlapping the BMAL1 cistrome during light phase; SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in peripheral tissues, alters hepatic metabolome rhythmicity, and disrupts cell-autonomous metabolite synchronization; SRC-2 itself is targeted by BMAL1:CLOCK in a feedforward loop.","method":"ChIP-seq (genome-wide), SRC-2 knockout mice, wheel-running behavioral assays, metabolomics, circadian gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq plus in vivo KO with behavioral and metabolic phenotypes","pmids":["24529706"],"is_preprint":false},{"year":2015,"finding":"SRC-2 (NCOA2) drives glutamine-dependent de novo lipogenesis in prostate cancer cells via reductive carboxylation of α-ketoglutarate to generate citrate through retrograde TCA cycling; SRC-2 coactivates SREBP-1 to enhance lipogenic enzyme expression; mTORC1-dependent phosphorylation activates SRC-2 in response to glutamine-mediated nutrient signaling; SRC-2 inhibition in murine models severely attenuates prostate cancer survival, growth, and metastasis.","method":"Metabolic flux analysis (13C-glutamine tracing), co-immunoprecipitation (SRC-2–SREBP-1), mTORC1 inhibition, murine xenograft/metastasis models, metabolic profiling of human tumor specimens","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — metabolic tracer experiments + Co-IP + in vivo models","pmids":["25664849"],"is_preprint":false},{"year":2015,"finding":"NCOA2 inhibits Wnt/β-catenin signaling in colorectal cancer cells 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 lacking functional domains) impairs pro-tumorigenic phenotypes; NCOA2 knockdown in normal colonocytes has opposite pro-tumorigenic effects.","method":"Overexpression and knockdown of NCOA2 and LACTB2-NCOA2 fusion, Wnt pathway gene expression analysis, in vitro proliferation/invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with pathway analysis, single lab","pmids":["25823027"],"is_preprint":false},{"year":2015,"finding":"NcoA2 (NCOA2) inhibits HIF-1α activation through competition with HIF-1α for ARNT binding; NcoA2 overexpression downregulates HRE transactivation by competing with HIF-1α and AhR to form protein complexes with ARNT; both NcoA2 knockdown and overexpression inhibit endothelial cell tube formation in vitro and vascularization in an in vivo plug assay; B[a]P decreases NcoA2 protein via AhR degradation, affecting this regulatory axis.","method":"Co-immunoprecipitation of NcoA2 with ARNT/HIF-1α/AhR, reporter assays (HRE, XRE), siRNA knockdown, in vitro tube formation, in vivo Matrigel plug assay","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP demonstrating competition for ARNT binding, in vivo functional assay","pmids":["26350169"],"is_preprint":false},{"year":2016,"finding":"GRIP1 (NCOA2) controls macrophage polarization via a GR-independent pathway by serving as a coactivator for KLF4 (a driver of tissue-resident macrophage differentiation); obese mice with conditional macrophage-specific GRIP1 deletion develop massive macrophage infiltration, inflammation, fatty livers, hyperglycemia, and insulin resistance, establishing GRIP1 as a critical regulator of immunometabolism through distinct KLF4- and GR-dependent transcriptional mechanisms.","method":"Conditional macrophage-specific GRIP1 knockout (Cre-lox), IL4 stimulation assays, reporter assays, diet-induced obesity model, metabolic phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with in vivo metabolic disease model and mechanistic pathway identification","pmids":["27464507"],"is_preprint":false},{"year":2017,"finding":"GRIP1 (NCOA2) is phosphorylated at an N-terminal serine cluster by CDK9, which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes; phosphorylation produces distinct GRE-specific GRIP1 phospho-isoforms that potentiate GRIP1 coactivator but not corepressor properties; phospho-GRIP1 and CDK9 are not detected at GR transrepression sites near pro-inflammatory genes, demonstrating that GR restricts GRIP1 coactivator activity to a subset of anti-inflammatory genes via CDK9-mediated phosphorylation.","method":"Co-immunoprecipitation of GR:GRIP1:CDK9 complex, phosphospecific antibodies, ChIP-seq (genome-wide), mutagenesis of phosphorylation sites, macrophage gene expression assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP + ChIP-seq + mutagenesis defining PTM-dependent functional switch","pmids":["29170386"],"is_preprint":false},{"year":2021,"finding":"PFKFB4 phosphorylates SRC-2/NCOA2 at Ser487, altering SRC-2 transcriptional activity; PFKFB4 and SRC-2 interact (co-immunoprecipitation); PFKFB4 promotes lung adenocarcinoma cell proliferation, migration, and invasion by phosphorylating SRC-2; phospho-SRC-2 transcriptionally upregulates CARM1, which is the downstream effector of the PFKFB4–SRC-2 axis on cancer progression.","method":"Co-immunoprecipitation, phosphorylation assay (Ser487), western blot for SRC-2 phosphorylation upon PFKFB4 knockdown, transcriptome sequencing, functional cancer cell assays","journal":"BMC pulmonary medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP + phosphorylation site identification + functional assays, single lab","pmids":["33593309"],"is_preprint":false},{"year":2022,"finding":"ETV6-NCOA2 fusion forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes; expression of ETV6-NCOA2 in nonthymic hematopoietic progenitors activates a lymphoid program while failing to repress myeloid genes (CSF1, MEF2C), causing an early immature T-cell developmental arrest; acquisition of activating NOTCH1 mutations transforms these cells into T/myeloid leukemia.","method":"Co-immunoprecipitation (ETV6-NCOA2/ETV6/p300 complex), mouse bone marrow transduction/transplantation, human cord blood CD34+ transduction with xenograft, gene expression profiling","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — Co-IP defining complex + in vivo mouse and human xenograft models with transcriptional mechanism","pmids":["34624096"],"is_preprint":false},{"year":2022,"finding":"HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets (ChIP-seq) and causes transactivation of HEY1 target genes (RNA-seq), significantly enhancing cell proliferation in iPSC-derived mesenchymal stem cells; the fusion specifically upregulates PDGFB and PDGFRA and dramatically increases phospho-AKT (Ser473) levels, effects not observed with wildtype HEY1 or wildtype NCOA2 alone, providing a mechanistic rationale for PDGF/PI3K/AKT inhibition in mesenchymal chondrosarcoma.","method":"ChIP-seq (genome-wide binding), RNA-seq (expression profiling), iPSC-MSC stable inducible expression system, phospho-AKT western blot, proliferation assays","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide ChIP-seq + RNA-seq + defined signaling readouts in relevant cellular model","pmids":["35342947"],"is_preprint":false},{"year":2023,"finding":"Ncoa2 (NCOA2) promotes CD8+ T cell-mediated antitumor immunity by upregulating PGC-1α expression to enhance mitochondrial function; T-cell activation-induced CREB phosphorylation triggers Ncoa2 recruitment to enhancers to stimulate PGC-1α transcription (ChIP); Ncoa2-deficient CD8+ T cells (Ncoa2fl/fl/CD4Cre) fail to increase mitochondrial mass, show impaired oxidative phosphorylation, and produce less IFNγ; forced PGC-1α expression rescues mitochondrial function and antitumor immunity.","method":"Conditional T cell-specific knockout (Ncoa2fl/fl/CD4Cre), ChIP showing Ncoa2 recruitment to PGC-1α enhancers, adoptive transfer experiments, mitochondrial function assays, MC38 tumor implantation model","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 — conditional KO + ChIP + adoptive transfer + rescue experiment","pmids":["37540802"],"is_preprint":false},{"year":2000,"finding":"SRC-1 and TIF2 (NCOA2) interact with HIF-1α and enhance its transactivation potential in a hypoxia-dependent manner; SRC-1 and TIF2 bind both C-terminal transactivation domains of HIF-1α; SRC-1 cooperates with CBP in synergy; the redox regulatory protein Ref-1 strongly potentiates SRC-1/CBP effects on HIF-1α, establishing TIF2/SRC-1 as components of the hypoxia signaling pathway.","method":"GST pulldown, mammalian reporter assays, co-immunoprecipitation, hypoxia induction experiments","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — pulldown + reporter assays demonstrating HIF-1α interaction and coactivation","pmids":["10594042"],"is_preprint":false},{"year":2002,"finding":"TIF2 (NCOA2) mediates synergy between RARα1 AF-1 and AF-2 by bridging both activation domains; bridging requires region A of RARα1 and the AD1 domain of TIF2; this RAR isotype-selective interaction requires additional unknown factors and is absent with SRC-1, establishing the first functional distinction between p160 family members for a specific NR isotype.","method":"Mammalian reporter assays, TIF2 domain mutants, comparison of SRC-1 vs TIF2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assays with domain mutants, single lab","pmids":["12149266"],"is_preprint":false},{"year":2002,"finding":"PIAS3 interacts with TIF2 (NCOA2) in vivo and in vitro through two distinct non-contiguous regions of TIF2 and a unique acidic domain of PIAS3 conserved in the PIAS family; PIAS3 modulates TIF2-mediated ligand-enhanced transcriptional activation positively or negatively depending on the steroid receptor examined.","method":"Co-immunoprecipitation, GST pulldown (in vitro binding), reporter assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal in vitro and in vivo binding assays with functional readout","pmids":["12208521"],"is_preprint":false},{"year":2004,"finding":"SRC-1 and TIF2 (NCOA2) have partially redundant functions in Sertoli cells: compound SRC-1/TIF2 knockout mice show that SRC-1 can partially compensate for TIF2 loss in mouse survival and growth, and TIF2/SRC-1 double deficiency uniformly accelerates the variable spermatogenesis defects of TIF2 single knockout, demonstrating functional redundancy in Sertoli cells alongside distinct physiological roles.","method":"Compound double-knockout mouse genetic analysis, histological characterization of testes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic epistasis with compound mutants","pmids":["15070739"],"is_preprint":false},{"year":2006,"finding":"TIF2 deletion in mice causes adrenocortical insufficiency: TIF2−/− mice display altered expression of glucocorticoid-dependent HPA axis components, significantly lower basal corticosterone and blunted stress responses, pronounced structural and functional aberrations in the zona fasciculata, and altered expression of nuclear receptors DAX-1 and SF-1 in the adrenal cortex, demonstrating that TIF2 is required for normal adrenocortical development and steroid biosynthesis.","method":"TIF2 knockout mice, HPA axis assays (ACTH, corticosterone), StAR and 3β-HSD expression, adrenal histology, stress response testing","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with defined adrenocortical cellular and biochemical phenotypes","pmids":["17135362"],"is_preprint":false},{"year":2011,"finding":"SRC-2 (NCOA2) and SRC-3 interact with PPARγ to coordinate transcriptional circuits promoting adipogenesis; individual or combined knockdown of SRC-2 and SRC-3 equally inhibits lipid accumulation by preventing lipogenic gene engagement; SRC-2/SRC-3 knockdown increases phospho-PPARγ-Ser114 (an inhibitor of PPARγ transcriptional activity), indicating that SRC-2 promotes adipogenesis partly by attenuating inhibitory PPARγ phosphorylation.","method":"High-content imaging, siRNA knockdown, phospho-PPARγ western blot, lipogenic gene expression assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with phosphorylation readout, single lab","pmids":["21220509"],"is_preprint":false}],"current_model":"NCOA2 (TIF2/GRIP1/SRC-2) is a 160 kDa p160 family nuclear receptor coactivator that binds liganded nuclear receptors through three LxxLL NR-box motifs in its receptor interaction domain, bridges receptor AF1 and AF2 activation functions to amplify transcription, and recruits secondary coactivators (CBP/p300 via AD1; CARM1, PRMT1 via AD2); it is regulated by SUMO-1 modification at Lys-239/731/788, ubiquitin-proteasome degradation triggered by PKA, and CDK9-mediated phosphorylation that selectively potentiates its coactivator (but not corepressor) function at GR-activated anti-inflammatory genes; NCOA2 also serves as a GR corepressor at AP-1 and NF-κB tethering elements through a unique repression domain absent from other p160 members, and performs physiological roles in energy homeostasis (hepatic glucose production via RORα–G6Pase, adaptive thermogenesis via SRC-1/PGC-1α balance, circadian rhythm via BMAL1:CLOCK coactivation), male fertility, adrenocortical development, macrophage polarization, and CD8+ T cell mitochondrial function via PGC-1α upregulation; oncogenic fusions (MOZ-TIF2, HEY1-NCOA2, ETV6-NCOA2, PAX3-NCOA2) co-opt the NCOA2 activation domains to drive leukemia or sarcoma through CBP recruitment, HEY1-target transactivation, or PDGF/PI3K/AKT pathway activation."},"narrative":{"teleology":[{"year":1996,"claim":"Cloning of TIF2/GRIP1 established that a dedicated 160 kDa nuclear protein mediates agonist- and AF-2-dependent coactivation of multiple nuclear receptors, resolving how NR ligand-binding domains transmit activation signals to the transcriptional machinery.","evidence":"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, and squelching assays in mammalian cells","pmids":["8670870","8643509"],"confidence":"High","gaps":["Structural basis of NR–TIF2 interaction undefined","Downstream effector mechanism unknown","Relative contribution versus other coactivators untested"]},{"year":1997,"claim":"Identification of three LxxLL NR-box motifs as the minimal units for NR interaction explained how a single coactivator recognizes diverse receptor dimers, with individual boxes showing receptor-selective preferences and cooperative binding enabling allosteric communication within heterodimers.","evidence":"NR-box mutagenesis combined with yeast two-hybrid and GST pulldown across multiple NR pairs","pmids":["9742117","9111344"],"confidence":"High","gaps":["No atomic-resolution structure of NR-box in complex with LBD","Auxiliary interaction domains not yet mapped"]},{"year":1998,"claim":"Functional dissection of AD1 and AD2 output domains revealed that NCOA2 activates transcription through two separable mechanisms—CBP/p300 recruitment (AD1) and a CBP-independent pathway (AD2)—establishing NCOA2 as a scaffold that integrates multiple chromatin-modifying activities.","evidence":"Mutagenesis separating AD1-CBP interaction from AD2, dominant-negative NID peptide in mammalian reporter assays","pmids":["9430642"],"confidence":"High","gaps":["AD2 effector unidentified","Relative contributions of AD1 versus AD2 at native genes unknown"]},{"year":1999,"claim":"Discovery of CARM1 as the AD2-recruited arginine methyltransferase completed the mechanistic picture of both NCOA2 output arms, demonstrating that NCOA2 couples NR activation to histone H3 arginine methylation via its C-terminal domain.","evidence":"Yeast two-hybrid, in vitro methyltransferase reconstitution, CARM1 SAM-binding mutant abolishing coactivation","pmids":["10381882"],"confidence":"High","gaps":["In vivo ChIP confirmation at native loci not yet performed","Specificity of CARM1 histone substrate in NR-regulated chromatin unclear"]},{"year":1999,"claim":"Mapping of an auxiliary NID (NIDaux) and demonstration that NCOA2 binds both NR AF-1 and AF-2 domains established that NCOA2 possesses dual signal-input surfaces, enabling it to bridge N- and C-terminal receptor activation domains for synergistic transcription.","evidence":"Deletion and point mutagenesis with GST pulldown and mammalian two-hybrid for GR, AR, and other NRs","pmids":["9920895","10454563"],"confidence":"High","gaps":["Structural basis of AF-1 binding unresolved","Whether bridging occurs simultaneously in vivo not confirmed"]},{"year":2001,"claim":"ChIP-based recruitment of GRIP1 to GR-repressed AP-1 elements overturned the assumption that p160 proteins are exclusively coactivators, revealing that NCOA2 can function as a GR corepressor at tethering GREs—a property later mapped to a unique repression domain absent from SRC-1 and SRC-3.","evidence":"ChIP at collagenase-3 promoter in U2OS cells, dominant-negative GRIP1 fragments, Gal4-tethered repression domain mapping","pmids":["11689447","12481024"],"confidence":"High","gaps":["Identity of downstream repression effectors unknown","Whether the repression domain recruits HDACs or other factors untested"]},{"year":2002,"claim":"Knockout mouse studies established non-redundant physiological roles for NCOA2: male fertility (Sertoli cell function), female fertility (decidual placentation), energy homeostasis (antagonism of SRC-1/PGC-1α thermogenic axis), and adrenocortical steroidogenesis, distinguishing NCOA2 from other p160 members in vivo.","evidence":"Global TIF2-knockout mice with histological, metabolic, and reproductive phenotyping; compound SRC-1/TIF2 double knockouts","pmids":["12138202","12507421","15070739","17135362"],"confidence":"High","gaps":["Cell-type-specific contributions not dissected with conditional alleles at this stage","Downstream target genes mediating each phenotype largely unidentified"]},{"year":2002,"claim":"Identification of SUMO-1 conjugation at K239/K731/K788 and its requirement for AR-dependent coactivation and nuclear colocalization introduced post-translational regulation as a layer controlling NCOA2 function, later complemented by discovery of PKA-triggered ubiquitin-proteasomal degradation.","evidence":"Site-directed mutagenesis of SUMO sites with confocal microscopy and reporter assays; pulse-chase and ubiquitin co-IP with proteasome inhibitors","pmids":["12060666","15347661"],"confidence":"High","gaps":["SUMO E3 ligase(s) responsible not identified","Interplay between sumoylation and ubiquitination unclear"]},{"year":2002,"claim":"The crystal structure of the GR LBD–dexamethasone–TIF2 NR-box peptide complex provided the first atomic view of LxxLL-motif recognition by a steroid receptor, revealing charge-clamp contacts and a novel GR dimerization interface.","evidence":"X-ray crystallography at atomic resolution with functional validation of dimer interface mutations","pmids":["12151000"],"confidence":"High","gaps":["Full-length NCOA2 structure unavailable","How auxiliary NID and AF-1 binding surfaces are spatially arranged relative to the LxxLL-clamp unknown"]},{"year":2003,"claim":"Demonstration that the MOZ-TIF2 fusion causes AML in mice and requires both the MOZ nucleosome-recognition motif and the TIF2 CBP-interaction domain for transformation established the mechanistic paradigm for NCOA2-containing oncogenic fusions: aberrant chromatin targeting coupled to CBP sequestration.","evidence":"Murine bone marrow transplantation with domain-deletion mutants of MOZ-TIF2","pmids":["12676584","15657427"],"confidence":"High","gaps":["Direct transcriptional targets of MOZ-TIF2 not yet genome-widely mapped","Whether CBP sequestration alone suffices or additional MOZ targets contribute unclear"]},{"year":2008,"claim":"Liver-specific SRC-2 ablation producing a glycogen storage disease phenotype through loss of RORα-dependent G6Pase expression placed NCOA2 as a central regulator of hepatic glucose homeostasis, expanding its physiological scope beyond reproduction and thermogenesis.","evidence":"Whole-body and liver-specific conditional knockout mice with glucose metabolism phenotyping and RORα coactivation reporter assays","pmids":["19039140"],"confidence":"High","gaps":["Whether other RORα target genes contribute to the phenotype untested","Redundancy with SRC-1/SRC-3 in liver not fully explored"]},{"year":2012,"claim":"Conditional macrophage-specific deletion proved GRIP1 is essential for GR-mediated repression of NF-κB targets in vivo, with GRIP1-deficient mice hypersensitive to LPS shock, definitively establishing NCOA2's corepressor function as physiologically critical for glucocorticoid anti-inflammatory action.","evidence":"Hematopoietic-cell-restricted Cre-lox knockout, genome-wide RNA-seq, LPS endotoxemia model","pmids":["22753499"],"confidence":"High","gaps":["Which specific genes drive lethality not pinpointed","Whether pharmacological GR ligands can bypass GRIP1 requirement untested"]},{"year":2014,"claim":"Genome-wide ChIP-seq showing diurnal NCOA2 recruitment overlapping the BMAL1 cistrome, combined with behavioral and metabolomic disruption in knockout mice, established NCOA2 as a core circadian coactivator linking clock transcription to peripheral metabolite rhythmicity.","evidence":"ChIP-seq for SRC-2 across circadian cycle, wheel-running behavioral assays, hepatic metabolomics in SRC-2 KO mice","pmids":["24529706"],"confidence":"High","gaps":["Whether NCOA2 acetylation or phosphorylation oscillates with clock phase unknown","Relative contribution versus other BMAL1 coactivators not quantified"]},{"year":2017,"claim":"Discovery that CDK9 phosphorylates GRIP1 within GR:GRIP1:CDK9 complexes and that phospho-GRIP1 selectively potentiates coactivator but not corepressor functions explained how a single cofactor can perform opposite transcriptional roles at different GR target genes, resolving a long-standing mechanistic paradox.","evidence":"Co-IP of ternary complex, phosphospecific antibodies, ChIP-seq at GR-activated versus GR-repressed loci, phosphosite mutagenesis in macrophages","pmids":["29170386"],"confidence":"High","gaps":["CDK9 recruitment mechanism to the complex unresolved","Whether other kinases contribute at different gene sets untested"]},{"year":2022,"claim":"Genome-wide characterization of the HEY1-NCOA2 fusion demonstrated it converts HEY1 from a repressor to a transactivator at promoter-proximal sites, activating PDGFB/PDGFRA and PI3K/AKT signaling, providing the first mechanistic rationale for targeted therapy in mesenchymal chondrosarcoma.","evidence":"ChIP-seq and RNA-seq in iPSC-derived mesenchymal stem cells expressing inducible HEY1-NCOA2, phospho-AKT readouts","pmids":["35342947"],"confidence":"High","gaps":["In vivo tumor model with fusion expression not reported","Whether PI3K/AKT inhibition is curative or only cytostatic unknown"]},{"year":2023,"claim":"Conditional T-cell-specific knockout revealed that NCOA2 sustains CD8+ T cell antitumor immunity by driving PGC-1α-dependent mitochondrial biogenesis, with rescue experiments confirming the NCOA2→PGC-1α axis as the critical pathway, expanding NCOA2 function into adaptive immunity.","evidence":"Ncoa2fl/fl/CD4Cre mice, ChIP showing NCOA2 at PGC-1α enhancers, MC38 tumor model, PGC-1α rescue of mitochondrial function","pmids":["37540802"],"confidence":"High","gaps":["Whether NCOA2 regulates CD4+ T cell or other lymphocyte subsets similarly untested","Upstream signals besides CREB phosphorylation not defined"]},{"year":null,"claim":"A full-length structural model of NCOA2, the identity of direct enzymatic targets of the repression domain, and the basis for gene-specific phospho-isoform deployment remain major unresolved questions.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length cryo-EM or X-ray structure exists","Repression domain effector mechanism unknown","Phospho-isoform determinants at individual genomic loci not decoded"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,4,8,10,11,13,30,41,45,50]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,8,10,11,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,16,17]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[17,35]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,4,8,10,11,13,30,41,45,50]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[40,42,49]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,37,45,50]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,30,32,42]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,39]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[41]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,18,31,34,38,40,48,49]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16,20]}],"complexes":["p160/NR coactivator complex","GR:GRIP1:CDK9 complex","MOZ-TIF2/BRPF1 complex"],"partners":["CBP","CARM1","NR3C1","ESR1","BMAL1","KLF4","CTNNB1","PPARG"],"other_free_text":[]},"mechanistic_narrative":"NCOA2 (TIF2/GRIP1/SRC-2) is a p160 family transcriptional coactivator that bridges liganded nuclear receptors to chromatin-modifying machinery, binding receptor AF-2 (and in some cases AF-1) activation functions through LxxLL NR-box motifs and recruiting secondary coactivators CBP/p300 via its AD1 domain and arginine methyltransferases CARM1/PRMT1 via AD2 [PMID:8670870, PMID:9742117, PMID:9430642, PMID:10381882]. Uniquely among p160 members, NCOA2 possesses an intrinsic repression domain that mediates GR transrepression at AP-1 and NF-κB tethering elements—a function critical for glucocorticoid anti-inflammatory signaling in macrophages—and its coactivator versus corepressor output is selectively governed by CDK9-mediated phosphorylation and regulated by SUMO-1 conjugation and PKA-triggered proteasomal degradation [PMID:12481024, PMID:22753499, PMID:29170386, PMID:12060666, PMID:15347661]. Beyond steroid receptor signaling, NCOA2 coactivates BMAL1:CLOCK to synchronize circadian gene expression, drives hepatic glucose production through RORα-dependent G6Pase transcription, controls energy homeostasis by antagonizing SRC-1/PGC-1α thermogenic programs, promotes CD8+ T cell mitochondrial fitness via PGC-1α upregulation, and regulates macrophage polarization through KLF4 coactivation [PMID:24529706, PMID:19039140, PMID:12507421, PMID:37540802, PMID:27464507]. Oncogenic NCOA2 fusions—MOZ-TIF2 in AML, HEY1-NCOA2 in mesenchymal chondrosarcoma, ETV6-NCOA2 in T-cell leukemia, and PAX3-NCOA2 in rhabdomyosarcoma—co-opt its CBP-recruiting AD1 domain or activation functions to drive aberrant transcription and signaling through PDGF/PI3K/AKT or HOX gene deregulation [PMID:12676584, PMID:35342947, PMID:34624096, PMID:24213582]."},"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). 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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, establishing it as a transcriptional mediator of NR AF-2.\",\n      \"method\": \"In vivo interaction assays, in vitro binding to LBDs, transient transfection reporter assays, squelching assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (in vivo, in vitro, functional reporter) in founding paper, widely replicated\",\n      \"pmids\": [\"8670870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"GRIP1 (mouse ortholog of TIF2/NCOA2) interacts with hormone-binding domains (HBDs) of glucocorticoid, estrogen, androgen, thyroid, vitamin D, retinoic acid, and retinoid X receptors in a hormone-dependent manner, and dramatically enhances their transcriptional activation function in yeast as a coactivator; experiments with GR truncation and point mutants demonstrated GRIP1 specifically interacts with and enhances the C-terminal AF-2 but not AF-1 transactivation domain.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, yeast transcriptional assays, mammalian cell transfection, receptor truncation/point mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including mutagenesis across multiple receptor subtypes, foundational paper\",\n      \"pmids\": [\"9111344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Three NR box (LXXLL) motifs in the receptor interaction domain (RID) of TIF2 are individually necessary and collectively sufficient for interaction with nuclear hormone receptors; individual NR boxes display preferences for certain receptors, and two TIF2 molecules can cooperatively bind a heterodimeric nuclear receptor complex, indicating allosteric effects upon coactivator binding.\",\n      \"method\": \"NR box mutagenesis, in vitro binding competition assays, cooperative binding experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with systematic mutagenesis\",\n      \"pmids\": [\"9742117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A novel MOZ-TIF2 fusion protein arising from inv(8)(p11q13) in acute myeloid leukemia retains the histone acetyltransferase homology domains of MOZ and the CBP-binding domain (AD1) of TIF2, suggesting leukemogenesis proceeds through recruitment of CBP by MOZ-TIF2 and abnormal histone acetylation.\",\n      \"method\": \"FISH, Southern blotting, RT-PCR, fusion protein structural analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization of fusion protein structure; mechanism partially inferred\",\n      \"pmids\": [\"9558366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SRC-1 and GRIP1 associate with HNF4 in vivo and enhance its transactivation potential; the AF-2 domain of HNF4 is required for this interaction and for transcriptional potentiation; GRIP1 and SRC-1 overexpression enhances HNF1 gene promoter expression in an HNF4-binding-site-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (in vivo association), transient transfection reporter assays, promoter-deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus functional reporter, single lab\",\n      \"pmids\": [\"9812974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"An auxiliary NR interaction domain (NIDaux, aa 1011–1121) in GRIP1, distinct from the central NID, is required in vitro and in vivo for efficient interaction with a subset of nuclear receptors including GR, AR, and RARα; NID and NIDaux must act in cis but do not need to be contiguous; the p300 interaction function within this region is separable from GR-binding function by mutagenesis.\",\n      \"method\": \"In vitro pull-down, mammalian two-hybrid, deletion/point mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro and in vivo assays with systematic deletion/mutagenesis\",\n      \"pmids\": [\"9920895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIF2 can simultaneously interact with both the isolated N-terminal AF1 and C-terminal AF2 of ERα in mammalian cells and in vitro, bridging both receptor domains; concomitant interaction results in synergistic transcriptional activation, explaining AF1–AF2 synergy.\",\n      \"method\": \"Mammalian two-hybrid, in vitro binding, transient transfection reporter assays with AF1/AF2 interaction-deficient TIF2 mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structure-function with mutants, in vitro and cell-based assays\",\n      \"pmids\": [\"11265755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIF2/GRIP1 is recruited to the collagenase-3 AP-1 response element (col3A) and potentiates GR-mediated transcriptional repression in an agonist-dependent manner; GRIP1 mutants deficient in GR binding and coactivator functions are also defective for corepression, and a GRIP1 fragment containing the GR-interacting region acts as a dominant-negative for repression; repression by TR at the same element is GRIP1-independent.\",\n      \"method\": \"ChIP, transient transfection with GRIP1 mutants/dominant-negatives, reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus mutant functional analysis with multiple approaches\",\n      \"pmids\": [\"11689447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GRIP1 acts as a GR coactivator at classical GREs and as a GR corepressor at AP-1 tethering GREs (e.g., collagenase-3) and NF-κB tethering GREs (IL-8); the corepressor activity was mapped to a distinct GRIP1 domain separate from the two known activation domains AD1 and AD2; this corepression domain had intrinsic GR-independent repression activity and was absent in SRC1 and RAC3.\",\n      \"method\": \"Transient transfection with domain-specific GRIP1 mutants, Gal4-DNA binding domain fusions, reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mapping with multiple mutants, functional assays in same cell type across multiple response elements\",\n      \"pmids\": [\"12481024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2−/− mice are viable but display impaired fertility: males show spermiogenesis defects (teratozoospermia) and age-dependent testicular degeneration attributed to loss of TIF2 in Sertoli cells affecting adhesion to germ cells; females show placental hypoplasia due to loss of TIF2 in decidua stromal cells.\",\n      \"method\": \"Knockout mouse phenotypic analysis, histology, tissue-specific expression studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific phenotypic readouts in vivo\",\n      \"pmids\": [\"12138202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2−/− mice are protected against obesity and show enhanced adaptive thermogenesis; lack of TIF2 in white adipose tissue decreases PPARγ activity and reduces fat accumulation; in brown adipose tissue, TIF2 deletion facilitates SRC-1–PGC-1α interaction that induces PGC-1α thermogenic activity; SRC-1−/− mice conversely show reduced energy expenditure and obesity.\",\n      \"method\": \"Knockout mouse metabolic phenotyping, gene expression, protein interaction studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal phenotypes in two KO models with mechanistic protein interaction data\",\n      \"pmids\": [\"12507421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SUMO-1 is covalently attached to GRIP1 at lysines 239, 731, and 788; Lys-731 and Lys-788 reside in the NR interaction domain, and their substitution by arginines impairs GRIP1 colocalization with AR in nuclei and attenuates GRIP1-dependent enhancement of AR transcription; synergy with PIASxβ-mediated AR activation also requires these sites.\",\n      \"method\": \"Mutagenesis of SUMO-1 attachment sites, confocal colocalization, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of modification sites with functional and localization readouts\",\n      \"pmids\": [\"12060666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MOZ-TIF2 transforms hematopoietic cells in vitro and causes AML in a murine bone marrow transplant model; transformation requires the C2HC nucleosome recognition motif of MOZ (MOZ HAT activity is dispensable) and the TIF2 CBP interaction domain (CID), demonstrating that nucleosomal targeting by MOZ and CBP recruitment by TIF2 are both critical mechanistic requirements.\",\n      \"method\": \"In vitro transformation assays, murine bone marrow transplant AML model, domain deletion mutagenesis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo leukemia model with systematic domain mutagenesis\",\n      \"pmids\": [\"12676584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"cAMP-dependent protein kinase (PKA) induces ubiquitin-proteasome-mediated degradation of GRIP1; PKA activation increases ubiquitination of GRIP1 and shortens its half-life; PKA also regulates the intracellular distribution of GRIP1, stimulating its recruitment to subnuclear foci that colocalize with the proteasome.\",\n      \"method\": \"Pulse-chase experiments, proteasome inhibitors (MG132/lactacystin), temperature-sensitive E1 ubiquitin-activating enzyme cell line (ts20), co-immunoprecipitation with ubiquitin, GFP-GRIP1 live imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including genetic ubiquitination system, pulse-chase, imaging\",\n      \"pmids\": [\"15347661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GRIP1 serves as a GR corepressor at NF-κB binding sites; a yeast two-hybrid screen identified IRF3 as a binding partner of the GRIP1 corepression domain (RD); endogenous GRIP1 and IRF3 interact in mammalian macrophages; GR and IRF3 compete for GRIP1 binding, and GR activation or GRIP1 knockdown blocks IRF3-dependent gene expression, while GRIP1 overexpression rescues it, placing GRIP1 at the intersection of GR immunosuppression and TLR3-IRF3 innate immune signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, GRIP1 knockdown, overexpression in macrophages, reporter assays, knockout mouse experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP of endogenous proteins, KD/KO with defined signaling pathway readouts, competition assays\",\n      \"pmids\": [\"16362036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"beta-Catenin interacts directly with TIF2/GRIP1; both N- and C-terminal regions of beta-catenin are needed for optimal TIF2/GRIP1 interaction; beta-catenin and TIF2/GRIP1 can each mediate binding between the other and AR in a three-way complex that enhances ligand-dependent AR transcription; a beta-catenin C-terminal peptide that binds both TIF2 and AR acts as a dominant inhibitor of AR-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, point mutagenesis of beta-catenin, dominant-negative peptide experiments, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and pull-down with mutagenesis, single lab\",\n      \"pmids\": [\"16141201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GRIP1 acts as a corepressor for MyoD, while SRC1A and p/CIP act as coactivators; GRIP1 binds both NH2-terminal activation domain sites on MyoD as well as sites critical for p300 binding, suggesting GRIP1 competes with p300, SRC1A, and p/CIP for MyoD interaction to negatively regulate MyoD-mediated transcription.\",\n      \"method\": \"Mammalian two-hybrid, domain-specific binding assays, reporter assays with p160 family members\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — binding domain mapping and functional assays, single lab\",\n      \"pmids\": [\"15563453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STAMP, a new 1277-aa protein, associates with TIF2 and SRC-1 coactivators; STAMP selectively affects a subset of steroid/nuclear receptors including GR; transfected STAMP increases TIF2 effects in both GR-mediated repression and induction; endogenous STAMP colocalizes with GR in intact cells and is recruited to promoters of GR-induced and -repressed endogenous genes; STAMP siRNA knockdown reduces both induction and repression of endogenous genes.\",\n      \"method\": \"Co-immunoprecipitation, confocal colocalization, ChIP on endogenous promoters, siRNA knockdown, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP on endogenous genes, Co-IP, and siRNA with functional readout, single lab\",\n      \"pmids\": [\"17116691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GRIP1 directly interacts with RIP140 through its carboxyl-terminal AD2 domain and functions as a platform molecule; on the TR2 promoter, RA induces differential coregulator recruitment: a GRIP1/PCAF complex in undifferentiated preadipocytes (activation) versus a GRIP1/RIP140 complex in differentiated adipocytes (repression), demonstrating context-dependent cofactor exchange on GRIP1.\",\n      \"method\": \"In vitro protein interaction assays, ChIP on TR2 promoter, reporter assays in 3T3-L1 cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus in vitro binding with domain identification, single lab\",\n      \"pmids\": [\"17389641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRC-2 (NCOA2) ablation in mice causes a Von Gierke's disease-like glycogenopathy; SRC-2 controls hepatic glucose-6-phosphatase (G6Pase) expression by acting as a coactivator with the orphan nuclear receptor RORα; both whole-body and liver-specific SRC-2 knockout recapitulate the phenotype, demonstrating a direct role in hepatic glucose production.\",\n      \"method\": \"Whole-body and liver-specific conditional knockout mice, gene expression analysis, coactivator functional assays with RORα\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined biochemical and phenotypic readouts, replicated in two KO models\",\n      \"pmids\": [\"19039140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRC-1 and TIF2 modulate expression of uncoupling protein 3 (UCP3) in an antagonistic manner in skeletal muscle myofibers; selective ablation of TIF2 in skeletal muscle (TIF2(i)skm−/−) increases mitochondrial uncoupling and protects against sedentariness-induced metabolic decline; elevated SRC-1 levels in TIF2-deficient myofibers are mechanistically responsible for the metabolic changes.\",\n      \"method\": \"Conditional skeletal muscle-specific TIF2 knockout mice, metabolic phenotyping, gene expression, protein level quantification\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional KO with clear molecular mechanism (SRC-1/UCP3 axis)\",\n      \"pmids\": [\"21035760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GRIP1 knockdown in primary macrophages attenuates GR-mediated dose-dependent repression of NF-κB target genes; genome-wide transcriptome analysis shows broad derepression of LPS-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages; ChIP shows GRIP1 is recruited to p65-occupied NF-κB binding sites in conjunction with liganded GR; conditional GRIP1-deficient mice develop increased LPS-induced shock, confirming GRIP1 as a GR corepressor mediating anti-inflammatory actions in vivo.\",\n      \"method\": \"Conditional hematopoietic cell-restricted GRIP1 knockout, ChIP-seq, transcriptome analysis, LPS challenge in vivo\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO, ChIP, genome-wide transcriptomics with in vivo validation\",\n      \"pmids\": [\"22753499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DHHC5 and DHHC8 palmitoyl acyltransferases (PATs) specifically palmitoylate GRIP1b; palmitoylation requires a PDZ ligand unique to DHHC5/8; palmitoylated GRIP1b is targeted to trafficking endosomes and links endosomes to kinesin motors; GRIP1b palmitoylation has the highest turnover rate of reported proteins; palmitoylation increases GRIP1b's ability to accelerate AMPA-R recycling.\",\n      \"method\": \"Palmitoylation assays, PDZ binding mutagenesis, subcellular fractionation, live-cell imaging, AMPA-R recycling assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — identification of specific PATs, mechanistic mutagenesis, functional trafficking assays\",\n      \"pmids\": [\"22325201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIF2 N-terminal fragment (TIF2.0, aa 1–627) interacts with the GR AF1 domain (N-terminal domain) and increases the amount of α-helical structure in the resulting complex; TIF2 coactivator activity is observed in the absence of GR LBD in a manner requiring AF1, establishing that a second region of TIF2 directly modifies AF1 conformation.\",\n      \"method\": \"Mammalian two-hybrid, hydrogen-deuterium exchange mass spectrometry, circular dichroism/structural analysis, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural analysis (HDX-MS) plus functional assays, direct conformational change demonstrated\",\n      \"pmids\": [\"23132854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRC-2 (NCOA2) serves as an essential coactivator of the BMAL1:CLOCK heterodimer; genome-wide SRC-2 recruitment to the hepatic genome extensively overlaps with the BMAL1 cistrome during the light phase; SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in multiple peripheral tissues, disrupts the hepatic metabolome rhythmicity, and deregulates synchronization of cell-autonomous metabolites; SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop.\",\n      \"method\": \"SRC-2 knockout mice, ChIP-seq (genome-wide), circadian behavior assays, metabolomics, gene expression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with genome-wide ChIP-seq and metabolomics, multiple orthogonal approaches\",\n      \"pmids\": [\"24529706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NCoA2 (SRC-2) overexpression in murine prostate epithelium causes neoplasia and, combined with Pten deletion, promotes metastasis-prone cancer; NCoA2 depletion in PTEN-deficient mice prevents CRPC development; NCoA2 overexpression results in hyperactivation of PI3K/AKT and MAPK signaling in prostate tumors; androgen signaling suppresses NCoA2 expression while androgen deprivation upregulates it, creating a feedforward loop driving CRPC.\",\n      \"method\": \"Prostate-specific NCoA2 transgenic mice, Pten/NCoA2 compound knockouts, kinase pathway analysis (Western blot), human PCa sample analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse models with defined molecular pathway (PI3K/AKT) plus human validation\",\n      \"pmids\": [\"25295534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRC-2 (NCOA2) drives glutamine-dependent de novo lipogenesis supporting prostate cancer cell survival and metastasis; SRC-2 stimulates reductive carboxylation of α-ketoglutarate to citrate via retrograde TCA cycling; glutamine-mediated nutrient signaling activates SRC-2 via mTORC1-dependent phosphorylation, which then coactivates SREBP-1 to enhance lipogenic enzyme expression.\",\n      \"method\": \"Metabolic flux analysis, mTORC1 inhibition, SRC-2 KD/OE in cancer cells, murine tumor models, human prostate tumor metabolic profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — metabolic reconstitution, mTORC1-phosphorylation mechanism, multiple cancer models\",\n      \"pmids\": [\"25664849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GRIP1 serves as a coactivator for KLF4, a driver of tissue-resident macrophage differentiation, via a GR-independent pathway; conditional GRIP1 deletion in macrophages leads to massive inflammatory macrophage infiltration in metabolic tissues, fatty liver, hyperglycemia, and insulin resistance in obese mice, implicating GRIP1 as a critical regulator of macrophage polarization and immunometabolism.\",\n      \"method\": \"Conditional macrophage-specific GRIP1 knockout, macrophage polarization assays, reporter assays with KLF4, diet-induced obesity model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined transcriptional mechanism (GRIP1-KLF4 coactivation) and in vivo metabolic phenotype\",\n      \"pmids\": [\"27464507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase 9 (CDK9); CDK9 is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes; CDK9-mediated phosphorylation potentiates GRIP1 coactivator but not corepressor properties; phospho-GRIP1 and CDK9 are not detected at GR transrepression sites near pro-inflammatory genes, demonstrating GRE-specific functional diversification.\",\n      \"method\": \"Phosphospecific antibodies, co-immunoprecipitation, ChIP-seq, GRIP1 phospho-mutant functional assays, kinase inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq, phospho-mutant analysis, Co-IP of endogenous complexes, multiple cell types\",\n      \"pmids\": [\"29170386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A recurrent HEY1-NCOA2 in-frame fusion (HEY1 exon 4 fused to NCOA2 exon 13) was identified as the defining genetic event in mesenchymal chondrosarcoma; FISH and RT-PCR confirmed its presence in all tested mesenchymal chondrosarcomas but not in other chondrosarcoma subtypes.\",\n      \"method\": \"Exon array expression profiling, 5′ RACE, RT-PCR, FISH\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular identification of fusion with diagnostic validation across multiple cases\",\n      \"pmids\": [\"22034177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets (ChIP-seq) and transactivates HEY1 target genes; the fusion, but not wildtype HEY1 or NCOA2 alone, dramatically increases phospho-AKT (Ser473) levels and significantly enhances cell proliferation; PDGFB and PDGFRA were identified as direct HEY1-NCOA2 targets.\",\n      \"method\": \"iPSC-derived mesenchymal stem cells with inducible HEY1-NCOA2, ChIP-seq, RNA-seq, phospho-protein analysis, proliferation assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide ChIP-seq plus RNA-seq with functional validation in appropriate cellular context\",\n      \"pmids\": [\"35342947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRF-NCOA2 and TEAD1-NCOA2 fusion genes were identified in congenital/infantile spindle cell rhabdomyosarcoma (RMS); NCOA2 rearrangements were found exclusively in young children (not adults) with spindle cell RMS, suggesting a distinct molecular subtype.\",\n      \"method\": \"Next-generation RNA sequencing, FusionSeq analysis, FISH, RT-PCR, RACE\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular identification of recurrent fusions confirmed by FISH and RT-PCR\",\n      \"pmids\": [\"23463663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAX3-NCOA2 fusion promotes proliferation and inhibits myogenic differentiation of rhabdomyosarcoma cells: PAX3-NCOA2-expressing C2C12 cells grow faster, are more motile, less anchorage-dependent, progress more rapidly through G1/S, and show greater transcriptional activation at the PAX3 consensus binding site, while myogenic differentiation is impaired compared to control cells.\",\n      \"method\": \"Stable C2C12 myoblast cell lines, proliferation assays, migration assays, cell cycle analysis, reporter assays, nude mouse tumor formation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — stable cell lines with multiple functional assays, in vivo tumor formation\",\n      \"pmids\": [\"24213582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ETV6-NCOA2 fusion protein forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes; ectopic expression in mouse hematopoietic progenitors induces T/myeloid lymphoma with spontaneous Notch1-activating mutations; in human cord blood CD34+ progenitors, ETV6-NCOA2 plus nontransforming NOTCH1 mutant induces T/myeloid leukemia, recapitulating patient disease.\",\n      \"method\": \"Co-immunoprecipitation (ETV6-NCOA2/ETV6/p300 complex), bone marrow transplant leukemia models, human cord blood xenograft models, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of transcriptional complex, in vivo leukemia models in mouse and human xenograft, mechanistic transcriptional analysis\",\n      \"pmids\": [\"34624096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NCOA2 inhibits Wnt/β-catenin signaling by simultaneously upregulating inhibitors and downregulating stimulators of the Wnt/β-catenin pathway in colorectal cancer cells; wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impairs pro-tumorigenic phenotypes, while NCOA2 knockdown in normal colonocytes has opposite effects.\",\n      \"method\": \"Enforced expression and knockdown of NCOA2, Wnt/β-catenin pathway gene expression analysis, cell proliferation/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain and loss of function with pathway analysis, single lab\",\n      \"pmids\": [\"25823027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PFKFB4 interacts with SRC-2 (NCOA2) and phosphorylates it at Ser487, altering SRC-2 transcriptional activity; this PFKFB4-SRC-2 axis promotes lung adenocarcinoma cell proliferation, migration, and invasion; CARM1 is transcriptionally regulated by SRC-2 downstream of PFKFB4-mediated phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for phosphorylation at Ser487, transcriptome sequencing, functional cancer cell assays (CCK-8, transwell)\",\n      \"journal\": \"BMC pulmonary medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and phosphorylation Western blot with functional assays, single lab\",\n      \"pmids\": [\"33593309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ncoa2 promotes CD8+ T cell antitumor immunity by upregulating PGC-1α expression to enhance mitochondrial function; T-cell activation-induced CREB phosphorylation triggers Ncoa2 recruitment to PGC-1α enhancers; Ncoa2-deficient CD8+ T cells (Ncoa2fl/fl/CD4Cre) fail to increase mitochondrial mass, show impaired oxidative phosphorylation, and have defective IFNγ production; forced PGC-1α expression rescues all these defects.\",\n      \"method\": \"Conditional T-cell-specific Ncoa2 knockout, ChIP at PGC-1α enhancer, metabolic analysis, adoptive transfer tumor models, rescue by forced PGC-1α expression\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with ChIP, metabolic readouts, rescue experiment, in vivo adoptive transfer\",\n      \"pmids\": [\"37540802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Endogenous TIF2 forms nuclear foci in cells; GR is recruited to TIF2 foci upon agonist but not antagonist treatment; the coactivators p300 and PCAF are also recruited to TIF2 foci; TIF2 foci can recruit a microinjected GR-responsive DNA element, suggesting TIF2 provides a nuclear compartment for assembly of multi-protein transcriptional complexes.\",\n      \"method\": \"Immunofluorescence of endogenous proteins, microinjection of GRE-containing DNA, confocal microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct imaging of endogenous proteins plus microinjection, single lab\",\n      \"pmids\": [\"15207724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MOZ-TIF2 fusion protein is generated from inv(8)(p11q13) in acute mixed lineage leukemia; the fusion contains MOZ zinc finger, nuclear localization, and HAT domains coupled to the TIF2 CBP interaction domain and activation domains, establishing that this AML subtype arises through fusion of HAT activity with transcriptional coactivation.\",\n      \"method\": \"FISH, Southern blotting, RT-PCR, fusion protein structural characterization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular methods confirming fusion structure, independent replication of MOZ-TIF2 fusion\",\n      \"pmids\": [\"9731070\"],\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) through the TIF2 CBP-binding domain (AD1); MOZ-TIF2 directly interacts with CBP in vivo (co-IP and FRET); MOZ-TIF2 displays aberrant nuclear distribution, reduces cellular CBP levels, and depletes CBP from PML bodies; the CBP-binding domain is also required for MOZ-TIF2-mediated extension of bone marrow cell proliferative potential.\",\n      \"method\": \"Co-immunoprecipitation, FRET, reporter assays with domain mutants, bone marrow colony assays, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, FRET for direct in vivo interaction, functional domain mutagenesis, cellular assays\",\n      \"pmids\": [\"15657427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MOZ-TIF2 fusion protein interacts with the transcription factor PU.1 to stimulate expression of the macrophage colony-stimulating factor receptor CSF1R; PU.1-deficient mice show that PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells; CSF1R-high cells, but not CSF1R-low cells, have potent leukemia-initiating activity.\",\n      \"method\": \"Co-immunoprecipitation, PU.1 KO mouse models, CSF1R reporter assays, conditional cell ablation using inducible suicide gene, leukemia stem cell transplantation assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, genetic KO epistasis, in vivo leukemia models with conditional cell ablation\",\n      \"pmids\": [\"20418886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ncoa2/Src-2 acts as a tumor suppressor in liver cancer; Sleeping Beauty mutagenesis screen identified Ncoa2 as a gene whose disruption cooperates with MYC-induced liver tumorigenesis; RNAi knockdown validates Ncoa2 as a tumor suppressor in liver progenitor cells; Ncoa2 deletion in mice predisposes to diethylnitrosamine-induced liver tumorigenesis.\",\n      \"method\": \"Sleeping Beauty transposon mutagenesis screen, RNAi knockdown, Ncoa2 KO mouse chemical carcinogenesis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — forward genetic screen validated by KO mouse phenotype and RNAi\",\n      \"pmids\": [\"22556267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NcoA2 (SRC-2) inhibits HIF-1α transactivation by competing with HIF-1α and AhR for complex formation with ARNT; NcoA2 overexpression downregulates HRE transactivation; NcoA2 knockdown and AhR knockdown decrease NcoA2 nuclear localization under hypoxic conditions; both knockdown and overexpression of NcoA2 inhibit endothelial cell tube formation in vitro and vascularization in vivo.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays (HRE, XRE), siRNA knockdown, tube formation assay, in vivo plug assay\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP showing protein complex competition, functional in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"26350169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PIAS3 interacts in vivo and in vitro with TIF2 through two distinct non-contiguous regions of TIF2 and a unique acidic domain of PIAS3; PIAS3 modulates TIF2-mediated ligand-enhanced transcriptional activation positively or negatively depending on the steroid receptor involved.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, reporter assays with PIAS3 domain mutants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP in vivo and in vitro binding with domain mapping, single lab\",\n      \"pmids\": [\"12208521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Endogenous GRIP1 in mammalian cells undergoes glucocorticoid-induced, GR interaction-dependent phosphorylation; six inducible and one constitutive phosphorylation sites were identified along with two putative kinases (casein kinase 2 and CDK9); phosphospecific antibodies combined with mutagenesis revealed phospho-GRIP1 is functionally relevant to GR-activated transcription and is recruited to native GR targets in a response element-specific manner.\",\n      \"method\": \"Mass spectrometry phosphosite identification, phosphospecific antibodies, ChIP at endogenous GR targets, GRIP1 phospho-mutant functional analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based site identification, ChIP on endogenous genes, phospho-mutant functional assays\",\n      \"pmids\": [\"22158970\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA2 (TIF2/GRIP1/SRC-2) is a p160 family transcriptional coregulator that binds ligand-activated nuclear receptors via three LXXLL NR-box motifs in its receptor interaction domain and an auxiliary NID, recruiting CBP/p300 through AD1 and CARM1/coactivators through AD2 to activate transcription; it can also act as a context-dependent corepressor (at AP-1 and NF-κB tethering GREs via a distinct repression domain), is regulated by phosphorylation (by CDK9 potentiating coactivator function) and SUMO-1 modification (modulating NR interaction), undergoes PKA-induced ubiquitin-proteasome degradation, coordinates energy homeostasis (glucose production via RORα/G6Pase, adipose thermogenesis, circadian rhythm via BMAL1:CLOCK coactivation, and cancer cell lipogenesis via mTORC1-dependent phosphorylation), and when fused to oncoproteins (MOZ, HEY1, ETV6, PAX3, SRF, TEAD1, AHRR, ESR1) drives hematologic malignancies or sarcomas through aberrant transcriptional activation of target genes.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification notes:**\n- Papers [5], [10], [14], [15], [24], [32], [35], [37], [39], [41], [42], [45], [49], [51], [57], [62], [63], [66], [77], [89], [93], [100] from the main corpus describe GRIP1 as the **glutamate receptor-interacting protein** (a PDZ scaffold protein encoded by *GRIP1* gene, not NCOA2). This is an **alias collision** — GRIP1 here refers to a completely different protein from the nuclear receptor coactivator GRIP1/TIF2/NCOA2.\n- Papers [54], [79] describe *Trypanosoma brucei* TIF2 — a telomere protein with no homology to mammalian NCOA2 → **SYMBOL COLLISION**, EXCLUDE.\n- Papers from additional corpus [8], [12]-[15], [17]-[19], [22]-[25], [27], [29] are general proteomics/genomics tools with no specific NCOA2 mechanistic findings → EXCLUDE.\n- Papers describing NCOA2 in cancer fusions ([7], [11], [19], [31], [52], [53], [55], [59], [68], [71], [80], [84], [90], [94], [96]) — keep only if they contain direct mechanistic findings about how NCOA2 protein works.\n\n```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 vivo in an agonist-dependent manner, binds directly to the ligand-binding domains (LBDs) of NRs 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, establishing it as a bona fide coactivator of NR AF-2.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, yeast two-hybrid, mammalian cell transfection reporter assays, squelching assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in a foundational paper; 904 citations indicating broad replication\",\n      \"pmids\": [\"8670870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"GRIP1 (mouse ortholog of NCOA2/TIF2) interacts with the hormone-binding domains (HBDs) of glucocorticoid, estrogen, and androgen receptors in a hormone-regulated manner in yeast two-hybrid and in vitro assays, and contains a transcriptional activation domain; overexpression squelches hormone-regulated and constitutive (CMV) reporter gene expression but not tRNA-driven expression, indicating interaction with the RNA Pol II machinery.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, mammalian reporter squelching assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, foundational paper with 598 citations\",\n      \"pmids\": [\"8643509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Full-length GRIP1/NCOA2 interacts in a hormone-dependent manner with all five steroid receptors and class II nuclear receptors (TRα, VDR, RARα, RXRα) via their hormone-binding domains; it serves as a transcriptional coactivator in yeast for all tested receptors but enhances only a subset in mammalian cells; experiments with GR truncation and point mutants demonstrate that GRIP1 interacts with and enhances specifically the C-terminal AF-2 but not the N-terminal AF-1 transactivation domain of GR.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, mammalian reporter assays, GR truncation/point mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus multiple receptor systems, 482 citations\",\n      \"pmids\": [\"9111344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The rat homolog of TIF2 (NCOA2) contains three short conserved NR box motifs (LXXLL) in its receptor interaction domain (NID); all three NR boxes are necessary and sufficient for interaction with nuclear hormone receptors, individual boxes display preference for certain receptors, and cooperative binding of two TIF2 molecules to a heterodimeric NR complex occurs even with only one cognate ligand, revealing an allosteric effect on the heterodimeric partner.\",\n      \"method\": \"Yeast two-hybrid, mutagenesis of NR boxes, GST pulldown, mammalian two-hybrid\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of defined motifs combined with binding assays\",\n      \"pmids\": [\"9742117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TIF2 (NCOA2) possesses a single NR interaction domain (NID) composed of three NR-interacting modules each containing the LxxLL (NR box) motif; the AD1 activation domain activity is mediated through CBP (and could not be separated mutationally from the CBP interaction domain), while AD2 activity does not involve CBP. An NID peptide acting as dominant-negative blocked AF-2 of several NRs in mammalian cells, confirming that endogenous TIF2 mediates NR AF-2 activity.\",\n      \"method\": \"Mutagenesis, mammalian and yeast transfection assays, dominant-negative peptide competition\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutational dissection of functional domains, replicated across systems; 430 citations\",\n      \"pmids\": [\"9430642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A novel chromosomal inversion inv(8)(p11q13) in acute myeloid leukemia fuses MOZ (a MYST-family histone acetyltransferase) to TIF2/NCOA2, producing a chimeric protein that retains MOZ HAT homology domains and the CBP-binding domain and activation domains of TIF2, implicating aberrant histone acetylation and CBP recruitment as potential leukemogenic mechanisms.\",\n      \"method\": \"FISH, Southern blot, RT-PCR, sequence analysis of fusion breakpoints\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning of fusion with domain analysis, single lab\",\n      \"pmids\": [\"9558366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SRC-1 and GRIP1 (NCOA2) associate with HNF4 in vivo (co-immunoprecipitation) and enhance its transactivation; the AF-2 domain of HNF4 is required for this interaction and for transcriptional potentiation; p300 synergizes with SRC-1 to further augment HNF4 activity; overexpression of SRC-1 or GRIP1 enhances expression from the HNF1 gene promoter in an HNF4-binding-site-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, mammalian reporter assays, promoter mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo co-IP plus functional reporter assays\",\n      \"pmids\": [\"9812974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GRIP-1 (NCOA2) functions as a coactivator for estrogen receptor (ER) even when AF-2 core sequences are mutated, indicating the HBD of ER contains multiple GRIP1 binding sites or contacts beyond AF-2; AF-2 deletion alters ligand pharmacology such that ER loses discrimination between agonists and antagonists, and on these mutants GRIP1 still coactivates irrespective of bound ligand.\",\n      \"method\": \"Mammalian reporter assays, ER AF-2 mutagenesis, ligand pharmacology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"9506965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GRIP1 (NCOA2) coactivation of CARM1 (coactivator-associated arginine methyltransferase 1) was discovered: CARM1 binds to the carboxyl-terminal region of p160 coactivators including GRIP1/TIF2, and enhances NR-mediated transcription only when GRIP1 or SRC-1a is coexpressed; CARM1 methylates histone H3 in vitro and mutation of its SAM-binding domain abolishes both methyltransferase and coactivator activities, establishing CARM1 as a secondary coactivator recruited through GRIP1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro histone methyltransferase assay, mutagenesis, mammalian reporter assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro methyltransferase + mutagenesis + cell-based assays; 991 citations\",\n      \"pmids\": [\"10381882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"An auxiliary NR interaction domain (NIDaux, aa 1011–1121) in GRIP1 (NCOA2) is required in vitro and in vivo for efficient interaction with a subset of NRs including GR, androgen receptor, and RARα; a second group of NRs (PR, RXRα, TRβ1, VDR) requires only the canonical NID; NID and NIDaux must act in cis for GR binding; the p300 interaction function within NIDaux is separable from its GR-binding contribution by mutagenesis.\",\n      \"method\": \"In vitro GST pulldown, mammalian two-hybrid, deletion and point mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis dissecting separable functions within a domain\",\n      \"pmids\": [\"9920895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"p160 coactivators including GRIP1 (NCOA2) contain two signal output domains: AD1 (which binds CBP/p300 via a conserved motif) and AD2 (which is CBP/p300-independent); the C-terminal region of GRIP1 also binds the N-terminal AF-1 domain of androgen receptor, showing that GRIP1 has two signal input domains (binding NR AF-2 and AF-1) and two signal output domains (AD1 and AD2) that play different relative roles for different NRs.\",\n      \"method\": \"Deletion mutagenesis, GST pulldown, mammalian reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic mutagenesis defining domain architecture; 208 citations\",\n      \"pmids\": [\"10454563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIF2 (NCOA2) can interact simultaneously with both the isolated N-terminus (AF1) and C-terminus (AF2) of ERα in transfected mammalian cells and in vitro, bridging both receptor domains; this concomitant interaction results in synergistic transcriptional activation, establishing that AF1–AF2 synergy is mediated by cooperative recruitment of TIF2.\",\n      \"method\": \"Mammalian two-hybrid, in vitro binding, reporter assays with TIF2 mutants deficient in AF1 or AF2 interaction\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of both AF1 and AF2 binding surfaces of TIF2 with functional readouts\",\n      \"pmids\": [\"11265755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIF2/GRIP1 (NCOA2) is recruited to the AP-1 site at the collagenase-3 (col3A) response element in human U2OS cells and potentiates GR-mediated transcriptional repression in the presence of GR agonist but not antagonist; GRIP1 mutants deficient in GR binding and coactivator functions are also defective for corepression; a GRIP1 fragment containing the GR-interacting region acts as dominant-negative for repression, revealing a corepressor function for GRIP1 at AP-1 tethering GREs.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter assays, dominant-negative GRIP1 fragments, mutant analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating in vivo recruitment plus functional mutagenesis\",\n      \"pmids\": [\"11689447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GRIP1 (NCOA2) acts as a GR coactivator at classical GREs and as a GR corepressor at AP-1 (collagenase-3) and NF-κB (IL-8) tethering GREs; the corepressor activity maps to a GRIP1 domain distinct from the two known activation domains (AD1, AD2); this repression domain has intrinsic GR-independent repression activity when recruited to DNA via Gal4-DBD; neither SRC1 nor RAC3 (SRC-3) possess this corepression domain, establishing GRIP1 as unique among p160 coactivators for GR-mediated transrepression.\",\n      \"method\": \"Domain mapping, Gal4-tethered reporter assays, comparative analysis of p160 family members\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional domain mapping with mutagenesis across multiple response elements\",\n      \"pmids\": [\"12481024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The SRC-2/TIF2 (NCOA2) knockout mouse is protected against obesity and displays enhanced adaptive thermogenesis, whereas SRC-1 knockout mice are prone to obesity. In white adipose tissue, TIF2 loss decreases PPARγ activity and reduces fat accumulation; in brown adipose tissue, TIF2 loss facilitates SRC-1–PGC-1α interaction, which induces PGC-1α thermogenic activity, revealing antagonistic roles of TIF2 and SRC-1 in energy homeostasis.\",\n      \"method\": \"Genetic knockout mice, PPARγ activity assays, co-immunoprecipitation of SRC-1 and PGC-1α, thermogenesis measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with mechanistic co-IP evidence; 365 citations\",\n      \"pmids\": [\"12507421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2/GRIP1 (NCOA2) knockout mice are viable but hypofertile in both sexes: male hypofertility results from spermiogenesis defects (teratozoospermia) and age-dependent testicular degeneration, with TIF2 essential for Sertoli cell adhesion to germ cells; female hypofertility results from placental hypoplasia requiring maternal TIF2 in decidua stromal cells, demonstrating distinct in vivo physiological roles from SRC-1 and p/CIP.\",\n      \"method\": \"Gene knockout (TIF2−/− mice), histological analysis, phenotypic characterization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular and tissue-level phenotypes\",\n      \"pmids\": [\"12138202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SUMO-1 is covalently attached to GRIP1 (NCOA2) at lysine residues 239, 731, and 788; Lys-731 and Lys-788 in the NR interaction domain (NID) are principal sites, and their substitution by arginine impairs GRIP1's ability to colocalize with androgen receptor in nuclei, attenuates AR-dependent transcription enhancement, and abolishes synergy with PIASxβ-mediated AR activation, establishing sumoylation as a PTM that modulates GRIP1 coactivator function.\",\n      \"method\": \"Site-directed mutagenesis of SUMO attachment sites, co-immunoprecipitation, confocal microscopy, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of specific SUMO sites with functional and localization readouts\",\n      \"pmids\": [\"12060666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2 (NCOA2) forms nuclear foci and can recruit GR to these foci upon agonist but not antagonist treatment; secondary coactivators p300 and PCAF are also recruited to TIF2 foci; TIF2 foci can recruit GR carrying a microinjected GR-responsive element, suggesting that TIF2 provides a pre-assembled nuclear compartment for multi-protein complex assembly required for GR-mediated gene activation.\",\n      \"method\": \"Immunofluorescence, live-cell imaging of nuclear foci, microinjection of GRE, confocal microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence (GRE recruitment)\",\n      \"pmids\": [\"15207724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MOZ-TIF2 fusion causes AML in a murine bone marrow transplant assay; the C2HC nucleosome recognition motif of MOZ is essential for transformation while MOZ HAT activity is dispensable; the TIF2 CBP-interaction domain (CID/AD1) is essential for transformation, establishing that nucleosomal targeting by MOZ and CBP recruitment by the TIF2 portion are both critical mechanistic requirements for MOZ-TIF2 leukemogenesis.\",\n      \"method\": \"Murine bone marrow transplantation, domain deletion/mutation analysis, in vitro colony assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo leukemia model with mutational dissection of essential domains\",\n      \"pmids\": [\"12676584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the human GR ligand-binding domain bound to dexamethasone and a coactivator motif derived from TIF2 (NCOA2) reveals the structural basis of LxxLL-motif recognition, an additional charge clamp determining coactivator binding selectivity, and a novel GR dimerization interface involving an intermolecular β-sheet.\",\n      \"method\": \"X-ray crystallography of GR LBD:TIF2 peptide complex, functional validation of dimer interface mutations\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation; 670 citations\",\n      \"pmids\": [\"12151000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GRIP1 (NCOA2) is ubiquitinated and degraded via the ubiquitin-proteasome pathway upon activation of cAMP-dependent protein kinase (PKA); PKA increases GRIP1 turnover (shown by pulse-chase), GRIP1 ubiquitination is increased by PKA overexpression (shown by co-immunoprecipitation with ubiquitin antibody), proteasome inhibitors block PKA-mediated degradation, and PKA stimulates recruitment of GRIP1 to subnuclear foci co-localizing with the proteasome.\",\n      \"method\": \"Pulse-chase, co-immunoprecipitation with ubiquitin, proteasome inhibitors (MG132, lactacystin), temperature-sensitive E1 mutant cells, GFP-GRIP1 live imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including ts20 E1-deficient cells and live imaging\",\n      \"pmids\": [\"15347661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GRIP1 (NCOA2) acts as a GR corepressor at the IRF3-responsive pathway: a yeast two-hybrid screen with the GRIP1 corepression domain identified IRF3 as a binding partner; endogenous GRIP1 and IRF3 interact in macrophages (co-immunoprecipitation); GR and IRF3 compete for GRIP1 binding; GR activation or GRIP1 knockdown blocks IRF3-dependent gene expression, while GRIP1 overexpression rescues it, establishing GRIP1 as a cofactor in innate immunity whose sequestration by GR suppresses TLR3-IRF3 signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, macrophage reporter assays, IRF3-deficient and MyD88-deficient mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic knockdown/overexpression, in vivo mouse models\",\n      \"pmids\": [\"16362036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GRIP1 (NCOA2) mediates the androgen receptor (AR) N-terminal/C-terminal (N/C) interaction: wild-type GRIP1 bridges AR-NTD and AR-LBD; co-expression of mutant GRIP1 lacking either AR interaction domain fails to restore N/C interaction; mutation of the AR-NTD FQNLF motif abolishing N/C interaction is rescued by GRIP1 coexpression, indicating that GRIP1 normally bridges the two AR domains to stabilize the N/C complex and facilitate secondary cofactor recruitment.\",\n      \"method\": \"Mammalian two-hybrid, AR N/C interaction assays, point mutagenesis of GRIP1 interaction domains\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiments with defined mutants\",\n      \"pmids\": [\"15843149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent activators (nuclear receptors, p53) by directly interacting with CBP in vivo (co-immunoprecipitation and FRET); the CBP-binding domain (AD1) of the TIF2 portion is required for this dominant-negative effect and for extending proliferative potential of murine bone marrow cells; MOZ-TIF2 displays aberrant nuclear distribution and reduces cellular CBP levels, depleting CBP from PML bodies.\",\n      \"method\": \"Co-immunoprecipitation, FRET, reporter assays, bone marrow progenitor proliferation assays, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — FRET + Co-IP demonstrating direct in vivo interaction, functional domain requirement\",\n      \"pmids\": [\"15657427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"β-catenin interacts directly with TIF2/GRIP1 (NCOA2) and with AR in a three-way complex; both N- and C-terminal regions of β-catenin are needed for optimal TIF2 interaction; β-catenin and TIF2 each mediate binding between the other and AR; a β-catenin C-terminal peptide binds TIF2 and AR but acts as a dominant inhibitor of ligand-dependent transcription, suggesting that AR–β-catenin–TIF2 form a ternary transcriptional complex.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, point mutagenesis, mammalian reporter assays, dominant-negative peptide analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding assays with mutagenesis, single lab\",\n      \"pmids\": [\"16141201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Among p160 coactivators, GRIP1 (NCOA2) uniquely acts as a corepressor (not coactivator) of MyoD-mediated transcription; SRC1A and p/CIP coactivate via distinct sites on MyoD's N-terminal activation domain, whereas GRIP1 binds both these regions and additionally interacts with MyoD sites critical for p300 binding, suggesting GRIP1 competes with p300 for MyoD interaction and thereby suppresses MyoD activity.\",\n      \"method\": \"Reporter assays, GST pulldown with MyoD deletion/point mutants, domain competition analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter plus binding domain mapping, single lab\",\n      \"pmids\": [\"15563453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GAC63, a novel coactivator, binds to the N-terminal region of GRIP1 (NCOA2) and the LBDs of some NRs; GAC63 enhances NR transcriptional activation in a hormone-dependent and GRIP1-dependent manner; endogenous GAC63 is recruited to the estrogen-responsive pS2 gene promoter in MCF-7 cells; siRNA knockdown of GAC63 inhibits ER-activated transcription, establishing GAC63 as a physiologically relevant component of the GRIP1-containing p160 coactivator complex.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, ChIP, siRNA knockdown, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus siRNA with functional readout\",\n      \"pmids\": [\"15988012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STAMP, a 1,277-aa protein, associates with TIF2 (NCOA2) and SRC-1 but is selective for a subset of receptors including GR; transfected STAMP increases TIF2 effects in GR-mediated repression and induction; siRNA knockdown of endogenous STAMP reduces both induction and repression of endogenous GR target genes; endogenous STAMP co-localizes with GR in intact cells and is recruited to promoters of GR-induced and -repressed genes by ChIP, establishing STAMP as a downstream cofactor of TIF2 in GR action.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ChIP, reporter assays, immunofluorescence co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and siRNA with endogenous gene readouts\",\n      \"pmids\": [\"17116691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GRIP1 (NCOA2) directly interacts with RIP140 through its carboxyl-terminal AD2 domain and serves as a platform molecule at the TR2 promoter; retinoic acid triggers exchange of PCAF (histone acetyltransferase) for RIP140 (histone deacetylase) on the GRIP1/TR2 complex, converting the locus from activation to repression and mediating the biphasic effect of RA on TR2 expression in preadipocytes versus adipocytes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assays, domain mapping of GRIP1–RIP140 interaction\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP showing coregulator exchange on promoter, Co-IP for direct interaction\",\n      \"pmids\": [\"17389641\"],\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 and SMRT for binding to GR and PR in mammalian two-hybrid and pull-down assays; NCoR RID#1 (but not RID#2) is necessary for binding to GR and PR; ChIP shows that exogenous TIF2.0 reduces NCoR occupancy at a PRE in the presence of antagonist; these results show that N-terminal TIF2 sequences (distinct from the canonical NID) compete with corepressors for receptor binding and oppose corepressor-mediated biological responses.\",\n      \"method\": \"Mammalian two-hybrid, pull-down, co-immunoprecipitation, ChIP, reporter assays, NCoR mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus biochemical assays, single lab\",\n      \"pmids\": [\"17571860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRC-2 (NCOA2) regulates fasting hepatic glucose release by controlling expression of glucose-6-phosphatase (G6Pase); SRC-2 directly coactivates the orphan nuclear receptor RORα to drive G6Pase expression; whole-body and liver-specific SRC-2 ablation in mice produces a Von Gierke's disease (glycogen storage disease-1a) phenotype with hepatic glycogen accumulation, positioning SRC-2 as a critical regulator of hepatic glucose production.\",\n      \"method\": \"Whole-body and conditional (liver-specific) knockout mice, reporter assays showing RORα coactivation, glucose metabolism phenotyping\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with mechanistic coactivation assay and disease phenotype; 136 citations\",\n      \"pmids\": [\"19039140\"],\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-deficient mice showed that PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells; CSF1R-high cells (but not CSF1R-low cells) possess leukemia-initiating activity; CSF1R inhibitors slowed MOZ-TIF2-induced leukemia progression.\",\n      \"method\": \"Co-immunoprecipitation of MOZ-TIF2 with PU.1, PU.1-knockout mouse model, conditional CSF1R-suicide transgene mouse, CSF1R inhibitor treatment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo genetic epistasis models defining mechanism\",\n      \"pmids\": [\"20418886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRC-1 and TIF2 (NCOA2) antagonistically regulate uncoupling protein 3 (UCP3) expression in skeletal muscle myofibers; selective ablation of TIF2 in adult skeletal muscle (TIF2(i)skm−/− mice) increases mitochondrial uncoupling, increases SRC-1 levels, and protects from sedentary-induced loss of oxidative capacity, diet-induced obesity, and type-2 diabetes onset.\",\n      \"method\": \"Inducible, muscle-specific TIF2 conditional knockout (Cre-lox), mitochondrial respiration measurements, expression analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined metabolic phenotype\",\n      \"pmids\": [\"21035760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A Sleeping Beauty transposon mutagenesis screen in MYC-driven liver cancer identified Ncoa2/Src-2 as a tumor suppressor; RNAi-mediated knockdown of Ncoa2 in liver progenitor cells accelerated tumorigenesis, and deletion of Ncoa2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis, establishing a tumor suppressor role for NCOA2 in liver cancer.\",\n      \"method\": \"Sleeping Beauty forward genetic screen in mice, RNAi knockdown in liver progenitor cells, chemical carcinogenesis (DEN) in Ncoa2-knockout mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic models (KO + chemical carcinogenesis) with functional validation\",\n      \"pmids\": [\"22556267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The HEY1-NCOA2 fusion, in which HEY1 exon 4 is fused in-frame to NCOA2 exon 13, is a recurrent gene fusion identified in mesenchymal chondrosarcoma; it was detected in all tested mesenchymal chondrosarcomas with definitive diagnosis but absent in other chondrosarcoma subtypes, establishing it as the defining molecular lesion of this tumor type.\",\n      \"method\": \"5' RACE, RT-PCR, FISH, Affymetrix Exon array-based fusion score analysis\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular methods confirming recurrent fusion across multiple tumor samples\",\n      \"pmids\": [\"22034177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Endogenous GRIP1 (NCOA2) undergoes glucocorticoid-induced, GR-interaction-dependent phosphorylation in mammalian cells; one constitutive and six inducible phosphorylation sites were identified, with casein kinase 2 and CDK9 as putative kinases; phosphospecific antibodies combined with mutagenesis demonstrated that phosphorylation at a cluster of closely spaced sites in an uncharacterized GRIP1 region is functionally relevant to GR-activated transcription and to GRE-specific recruitment of phospho-GRIP1 to native GR target genes.\",\n      \"method\": \"Mass spectrometry phosphoproteomics, phosphospecific antibody generation, site-directed mutagenesis, ChIP at endogenous GR targets\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS identification of sites + mutagenesis + ChIP at endogenous loci\",\n      \"pmids\": [\"22158970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Binding of the N-terminal region of TIF2 (TIF2.0) to the intrinsically disordered AF1 domain of GR is accompanied by an increase in α-helical structure in the complex (shown by biophysical analysis); TIF2 coactivator activity is observed in the absence of GR LBD in an AF1-dependent manner, demonstrating that TIF2 can directly bind and structurally reorganize GR AF1 to promote transcriptional activation independently of the classical LBD–NID interaction.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry, circular dichroism, mammalian reporter assays with GR truncations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — biophysical structural evidence of induced folding, single lab\",\n      \"pmids\": [\"23132854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional hematopoietic-cell-restricted deletion of GRIP1 (NCOA2) in adult mice demonstrates that GRIP1 is required in macrophages for GR-mediated repression of NF-κB target genes; genome-wide transcriptome analysis reveals broad derepression of LPS-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages; GRIP1-deficient mice are sensitized to LPS-induced shock, establishing that GRIP1 is essential for glucocorticoid anti-inflammatory actions in vivo.\",\n      \"method\": \"Conditional knockout (Cre-lox restricted to hematopoietic cells), genome-wide RNA-seq, LPS shock model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with genome-wide readout and in vivo inflammatory model\",\n      \"pmids\": [\"22753499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAX3-NCOA2 fusion gene promotes proliferation (faster growth, greater motility, anchorage independence, accelerated G1/S, greater PAX3-binding-site transcriptional activation) and inhibits myogenic differentiation of rhabdomyosarcoma cells compared to controls; in stable mouse myoblast C2C12 cells expressing PAX3-NCOA2, both tumorigenic properties are demonstrated in nude mouse xenografts.\",\n      \"method\": \"Stable cell line generation, proliferation/motility/anchorage assays, cell cycle analysis, luciferase reporter assays, nude mouse xenografts, differentiation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotypes with in vivo validation, single lab\",\n      \"pmids\": [\"24213582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MOZ-TIF2 forms a stable complex with BRPF1 (bromodomain-PHD finger protein 1) shown by immunoprecipitation; ChIP shows MOZ-TIF2 and BRPF1 interact with HOX gene loci in AML cells; BRPF1 depletion decreases MOZ localization on HOX genes and abrogates MOZ-TIF2 transformation ability; mutant MOZ-TIF2 lacking HAT activity cannot deregulate HOX genes or initiate leukemia, establishing that MOZ-TIF2/BRPF1 upregulates HOX genes via MOZ HAT-mediated histone acetylation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, HAT-activity mutant, in vitro transformation assays\",\n      \"journal\": \"International journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + Co-IP + functional mutagenesis, single lab\",\n      \"pmids\": [\"24258712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NCoA2/SRC-2 (NCOA2) overexpression in mouse prostate epithelium causes neoplasia and, combined with PTEN deletion, promotes metastasis-prone cancer; NCoA2 overexpression leads to hyperactivation of PI3K/AKT and MAPK signaling in murine prostate tumors; androgen signaling suppresses NCoA2 expression in human androgen-sensitive prostate cancer cells; NCoA2 depletion in PTEN-deficient mice prevents development of castration-resistant prostate cancer.\",\n      \"method\": \"Prostate-specific overexpression mouse model, PTEN-knockout combination, NCoA2 depletion in vivo, PI3K/AKT/MAPK signaling assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo genetic models with defined signaling pathway readouts\",\n      \"pmids\": [\"25295534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRC-2 (NCOA2) is an essential coactivator for BMAL1:CLOCK circadian transcription; genome-wide ChIP-seq shows diurnal SRC-2 recruitment extensively overlapping the BMAL1 cistrome during light phase; SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in peripheral tissues, alters hepatic metabolome rhythmicity, and disrupts cell-autonomous metabolite synchronization; SRC-2 itself is targeted by BMAL1:CLOCK in a feedforward loop.\",\n      \"method\": \"ChIP-seq (genome-wide), SRC-2 knockout mice, wheel-running behavioral assays, metabolomics, circadian gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq plus in vivo KO with behavioral and metabolic phenotypes\",\n      \"pmids\": [\"24529706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRC-2 (NCOA2) drives glutamine-dependent de novo lipogenesis in prostate cancer cells via reductive carboxylation of α-ketoglutarate to generate citrate through retrograde TCA cycling; SRC-2 coactivates SREBP-1 to enhance lipogenic enzyme expression; mTORC1-dependent phosphorylation activates SRC-2 in response to glutamine-mediated nutrient signaling; SRC-2 inhibition in murine models severely attenuates prostate cancer survival, growth, and metastasis.\",\n      \"method\": \"Metabolic flux analysis (13C-glutamine tracing), co-immunoprecipitation (SRC-2–SREBP-1), mTORC1 inhibition, murine xenograft/metastasis models, metabolic profiling of human tumor specimens\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — metabolic tracer experiments + Co-IP + in vivo models\",\n      \"pmids\": [\"25664849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NCOA2 inhibits Wnt/β-catenin signaling in colorectal cancer cells 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 lacking functional domains) impairs pro-tumorigenic phenotypes; NCOA2 knockdown in normal colonocytes has opposite pro-tumorigenic effects.\",\n      \"method\": \"Overexpression and knockdown of NCOA2 and LACTB2-NCOA2 fusion, Wnt pathway gene expression analysis, in vitro proliferation/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with pathway analysis, single lab\",\n      \"pmids\": [\"25823027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NcoA2 (NCOA2) inhibits HIF-1α activation through competition with HIF-1α for ARNT binding; NcoA2 overexpression downregulates HRE transactivation by competing with HIF-1α and AhR to form protein complexes with ARNT; both NcoA2 knockdown and overexpression inhibit endothelial cell tube formation in vitro and vascularization in an in vivo plug assay; B[a]P decreases NcoA2 protein via AhR degradation, affecting this regulatory axis.\",\n      \"method\": \"Co-immunoprecipitation of NcoA2 with ARNT/HIF-1α/AhR, reporter assays (HRE, XRE), siRNA knockdown, in vitro tube formation, in vivo Matrigel plug assay\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating competition for ARNT binding, in vivo functional assay\",\n      \"pmids\": [\"26350169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GRIP1 (NCOA2) controls macrophage polarization via a GR-independent pathway by serving as a coactivator for KLF4 (a driver of tissue-resident macrophage differentiation); obese mice with conditional macrophage-specific GRIP1 deletion develop massive macrophage infiltration, inflammation, fatty livers, hyperglycemia, and insulin resistance, establishing GRIP1 as a critical regulator of immunometabolism through distinct KLF4- and GR-dependent transcriptional mechanisms.\",\n      \"method\": \"Conditional macrophage-specific GRIP1 knockout (Cre-lox), IL4 stimulation assays, reporter assays, diet-induced obesity model, metabolic phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with in vivo metabolic disease model and mechanistic pathway identification\",\n      \"pmids\": [\"27464507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GRIP1 (NCOA2) is phosphorylated at an N-terminal serine cluster by CDK9, which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes; phosphorylation produces distinct GRE-specific GRIP1 phospho-isoforms that potentiate GRIP1 coactivator but not corepressor properties; phospho-GRIP1 and CDK9 are not detected at GR transrepression sites near pro-inflammatory genes, demonstrating that GR restricts GRIP1 coactivator activity to a subset of anti-inflammatory genes via CDK9-mediated phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation of GR:GRIP1:CDK9 complex, phosphospecific antibodies, ChIP-seq (genome-wide), mutagenesis of phosphorylation sites, macrophage gene expression assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP + ChIP-seq + mutagenesis defining PTM-dependent functional switch\",\n      \"pmids\": [\"29170386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PFKFB4 phosphorylates SRC-2/NCOA2 at Ser487, altering SRC-2 transcriptional activity; PFKFB4 and SRC-2 interact (co-immunoprecipitation); PFKFB4 promotes lung adenocarcinoma cell proliferation, migration, and invasion by phosphorylating SRC-2; phospho-SRC-2 transcriptionally upregulates CARM1, which is the downstream effector of the PFKFB4–SRC-2 axis on cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay (Ser487), western blot for SRC-2 phosphorylation upon PFKFB4 knockdown, transcriptome sequencing, functional cancer cell assays\",\n      \"journal\": \"BMC pulmonary medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + phosphorylation site identification + functional assays, single lab\",\n      \"pmids\": [\"33593309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ETV6-NCOA2 fusion forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes; expression of ETV6-NCOA2 in nonthymic hematopoietic progenitors activates a lymphoid program while failing to repress myeloid genes (CSF1, MEF2C), causing an early immature T-cell developmental arrest; acquisition of activating NOTCH1 mutations transforms these cells into T/myeloid leukemia.\",\n      \"method\": \"Co-immunoprecipitation (ETV6-NCOA2/ETV6/p300 complex), mouse bone marrow transduction/transplantation, human cord blood CD34+ transduction with xenograft, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP defining complex + in vivo mouse and human xenograft models with transcriptional mechanism\",\n      \"pmids\": [\"34624096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HEY1-NCOA2 fusion protein preferentially binds to promoter regions of canonical HEY1 targets (ChIP-seq) and causes transactivation of HEY1 target genes (RNA-seq), significantly enhancing cell proliferation in iPSC-derived mesenchymal stem cells; the fusion specifically upregulates PDGFB and PDGFRA and dramatically increases phospho-AKT (Ser473) levels, effects not observed with wildtype HEY1 or wildtype NCOA2 alone, providing a mechanistic rationale for PDGF/PI3K/AKT inhibition in mesenchymal chondrosarcoma.\",\n      \"method\": \"ChIP-seq (genome-wide binding), RNA-seq (expression profiling), iPSC-MSC stable inducible expression system, phospho-AKT western blot, proliferation assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide ChIP-seq + RNA-seq + defined signaling readouts in relevant cellular model\",\n      \"pmids\": [\"35342947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ncoa2 (NCOA2) promotes CD8+ T cell-mediated antitumor immunity by upregulating PGC-1α expression to enhance mitochondrial function; T-cell activation-induced CREB phosphorylation triggers Ncoa2 recruitment to enhancers to stimulate PGC-1α transcription (ChIP); Ncoa2-deficient CD8+ T cells (Ncoa2fl/fl/CD4Cre) fail to increase mitochondrial mass, show impaired oxidative phosphorylation, and produce less IFNγ; forced PGC-1α expression rescues mitochondrial function and antitumor immunity.\",\n      \"method\": \"Conditional T cell-specific knockout (Ncoa2fl/fl/CD4Cre), ChIP showing Ncoa2 recruitment to PGC-1α enhancers, adoptive transfer experiments, mitochondrial function assays, MC38 tumor implantation model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO + ChIP + adoptive transfer + rescue experiment\",\n      \"pmids\": [\"37540802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SRC-1 and TIF2 (NCOA2) interact with HIF-1α and enhance its transactivation potential in a hypoxia-dependent manner; SRC-1 and TIF2 bind both C-terminal transactivation domains of HIF-1α; SRC-1 cooperates with CBP in synergy; the redox regulatory protein Ref-1 strongly potentiates SRC-1/CBP effects on HIF-1α, establishing TIF2/SRC-1 as components of the hypoxia signaling pathway.\",\n      \"method\": \"GST pulldown, mammalian reporter assays, co-immunoprecipitation, hypoxia induction experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulldown + reporter assays demonstrating HIF-1α interaction and coactivation\",\n      \"pmids\": [\"10594042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIF2 (NCOA2) mediates synergy between RARα1 AF-1 and AF-2 by bridging both activation domains; bridging requires region A of RARα1 and the AD1 domain of TIF2; this RAR isotype-selective interaction requires additional unknown factors and is absent with SRC-1, establishing the first functional distinction between p160 family members for a specific NR isotype.\",\n      \"method\": \"Mammalian reporter assays, TIF2 domain mutants, comparison of SRC-1 vs TIF2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assays with domain mutants, single lab\",\n      \"pmids\": [\"12149266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PIAS3 interacts with TIF2 (NCOA2) in vivo and in vitro through two distinct non-contiguous regions of TIF2 and a unique acidic domain of PIAS3 conserved in the PIAS family; PIAS3 modulates TIF2-mediated ligand-enhanced transcriptional activation positively or negatively depending on the steroid receptor examined.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown (in vitro binding), reporter assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal in vitro and in vivo binding assays with functional readout\",\n      \"pmids\": [\"12208521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SRC-1 and TIF2 (NCOA2) have partially redundant functions in Sertoli cells: compound SRC-1/TIF2 knockout mice show that SRC-1 can partially compensate for TIF2 loss in mouse survival and growth, and TIF2/SRC-1 double deficiency uniformly accelerates the variable spermatogenesis defects of TIF2 single knockout, demonstrating functional redundancy in Sertoli cells alongside distinct physiological roles.\",\n      \"method\": \"Compound double-knockout mouse genetic analysis, histological characterization of testes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic epistasis with compound mutants\",\n      \"pmids\": [\"15070739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TIF2 deletion in mice causes adrenocortical insufficiency: TIF2−/− mice display altered expression of glucocorticoid-dependent HPA axis components, significantly lower basal corticosterone and blunted stress responses, pronounced structural and functional aberrations in the zona fasciculata, and altered expression of nuclear receptors DAX-1 and SF-1 in the adrenal cortex, demonstrating that TIF2 is required for normal adrenocortical development and steroid biosynthesis.\",\n      \"method\": \"TIF2 knockout mice, HPA axis assays (ACTH, corticosterone), StAR and 3β-HSD expression, adrenal histology, stress response testing\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined adrenocortical cellular and biochemical phenotypes\",\n      \"pmids\": [\"17135362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRC-2 (NCOA2) and SRC-3 interact with PPARγ to coordinate transcriptional circuits promoting adipogenesis; individual or combined knockdown of SRC-2 and SRC-3 equally inhibits lipid accumulation by preventing lipogenic gene engagement; SRC-2/SRC-3 knockdown increases phospho-PPARγ-Ser114 (an inhibitor of PPARγ transcriptional activity), indicating that SRC-2 promotes adipogenesis partly by attenuating inhibitory PPARγ phosphorylation.\",\n      \"method\": \"High-content imaging, siRNA knockdown, phospho-PPARγ western blot, lipogenic gene expression assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with phosphorylation readout, single lab\",\n      \"pmids\": [\"21220509\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA2 (TIF2/GRIP1/SRC-2) is a 160 kDa p160 family nuclear receptor coactivator that binds liganded nuclear receptors through three LxxLL NR-box motifs in its receptor interaction domain, bridges receptor AF1 and AF2 activation functions to amplify transcription, and recruits secondary coactivators (CBP/p300 via AD1; CARM1, PRMT1 via AD2); it is regulated by SUMO-1 modification at Lys-239/731/788, ubiquitin-proteasome degradation triggered by PKA, and CDK9-mediated phosphorylation that selectively potentiates its coactivator (but not corepressor) function at GR-activated anti-inflammatory genes; NCOA2 also serves as a GR corepressor at AP-1 and NF-κB tethering elements through a unique repression domain absent from other p160 members, and performs physiological roles in energy homeostasis (hepatic glucose production via RORα–G6Pase, adaptive thermogenesis via SRC-1/PGC-1α balance, circadian rhythm via BMAL1:CLOCK coactivation), male fertility, adrenocortical development, macrophage polarization, and CD8+ T cell mitochondrial function via PGC-1α upregulation; oncogenic fusions (MOZ-TIF2, HEY1-NCOA2, ETV6-NCOA2, PAX3-NCOA2) co-opt the NCOA2 activation domains to drive leukemia or sarcoma through CBP recruitment, HEY1-target transactivation, or PDGF/PI3K/AKT pathway activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NCOA2 (TIF2/GRIP1/SRC-2) is a p160-family transcriptional coactivator that integrates nuclear receptor signaling, chromatin remodeling, energy metabolism, circadian rhythm, and immune regulation. It binds ligand-activated nuclear receptors through three LXXLL NR-box motifs and an auxiliary NID, recruits CBP/p300 via its AD1 domain and CARM1 via AD2, and bridges receptor AF1 and AF2 domains to drive synergistic transcriptional activation; it also functions as a context-dependent corepressor at AP-1 and NF-κB tethering GREs through a distinct repression domain, mediating glucocorticoid anti-inflammatory actions in macrophages [PMID:8670870, PMID:9742117, PMID:12481024, PMID:22753499]. NCOA2 is regulated by CDK9-mediated phosphorylation that selectively potentiates coactivator but not corepressor function, by SUMO-1 conjugation that modulates nuclear receptor interaction, and by PKA-induced ubiquitin-proteasome degradation [PMID:29170386, PMID:12060666, PMID:15347661]. Physiologically, NCOA2 controls hepatic glucose production as a RORα coactivator, antagonizes SRC-1 to regulate adipose thermogenesis and skeletal muscle mitochondrial uncoupling, coactivates BMAL1:CLOCK to synchronize circadian metabolic programs, promotes CD8+ T cell antitumor function via PGC-1α-dependent mitochondrial biogenesis, and when fused to oncoproteins such as MOZ, HEY1, ETV6, or PAX3, drives acute myeloid leukemia, mesenchymal chondrosarcoma, or rhabdomyosarcoma through aberrant transcriptional activation and CBP sequestration [PMID:19039140, PMID:12507421, PMID:24529706, PMID:37540802, PMID:12676584, PMID:22034177, PMID:34624096].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The identity of transcriptional mediators linking nuclear receptor AF-2 to transcription was unknown; cloning of TIF2 established that a 160-kDa nuclear protein directly contacts NR ligand-binding domains in an agonist- and AF-2-dependent manner and possesses autonomous transactivation function, founding the p160 coactivator family.\",\n      \"evidence\": \"In vivo interaction assays, in vitro LBD binding, transfection reporter assays, squelching experiments\",\n      \"pmids\": [\"8670870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TIF2–NR interaction not resolved\", \"Which NR subtypes are preferred was unclear\", \"Downstream effectors of TIF2 transactivation not identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Whether TIF2/GRIP1 functioned broadly across NR classes or was receptor-specific was untested; GRIP1 was shown to interact with and enhance transcription of GR, ER, AR, TR, VDR, RAR, and RXR in a hormone-dependent, AF-2-specific manner, establishing it as a general NR coactivator.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, yeast/mammalian transcriptional assays, GR truncation/point mutants\",\n      \"pmids\": [\"9111344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of receptor selectivity among p160 family members not addressed\", \"AF-1 interaction not yet explored\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"The molecular determinants mediating NR recognition were undefined; systematic mutagenesis showed that three LXXLL NR-box motifs are individually necessary and collectively sufficient for NR binding, with individual boxes displaying receptor preferences, and two TIF2 molecules can cooperatively bind an NR heterodimer.\",\n      \"evidence\": \"NR-box mutagenesis, in vitro competition and cooperative binding assays\",\n      \"pmids\": [\"9742117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of NR-box–LBD complex not yet available\", \"How cooperativity is achieved structurally was unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"A pathogenic role for NCOA2 was first revealed when the MOZ-TIF2 fusion arising from inv(8)(p11q13) was identified in acute myeloid leukemia, coupling MOZ HAT/nucleosome recognition to TIF2's CBP-binding domain.\",\n      \"evidence\": \"FISH, Southern blot, RT-PCR, structural analysis of fusion in AML patients\",\n      \"pmids\": [\"9558366\", \"9731070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MOZ HAT activity or CBP recruitment is the transforming function was unknown\", \"Leukemia-initiating cell identity not established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Whether the central NID was the sole NR contact surface was unresolved; an auxiliary NID (aa 1011–1121) was identified that is required for efficient interaction with GR, AR, and RARα, with its p300-binding and GR-binding functions separable by mutagenesis.\",\n      \"evidence\": \"In vitro pull-down, mammalian two-hybrid, deletion/point mutagenesis\",\n      \"pmids\": [\"9920895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NIDaux contributes to corepressor function was untested\", \"Structural basis of NIDaux–NR contact not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"How NR AF1 and AF2 achieve transcriptional synergy was a long-standing question; TIF2 was shown to simultaneously contact both ER AF1 and AF2, physically bridging them and producing synergistic activation.\",\n      \"evidence\": \"Mammalian two-hybrid, in vitro binding, reporter assays with interaction-deficient TIF2 mutants\",\n      \"pmids\": [\"11265755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this bridging applies to all NRs was unclear\", \"Structural basis of simultaneous AF1/AF2 contact not determined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Whether GRIP1 was exclusively a coactivator was challenged when it was shown to be recruited to AP-1 response elements and to potentiate GR-mediated transcriptional repression in an agonist-dependent manner, establishing a dual coactivator/corepressor paradigm.\",\n      \"evidence\": \"ChIP at collagenase-3 AP-1 element, GRIP1 mutants/dominant-negatives, reporter assays\",\n      \"pmids\": [\"11689447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The domain mediating repression was not yet mapped\", \"Whether corepression extended to NF-κB targets was unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The corepressor activity was mapped to a distinct repression domain (RD) in GRIP1, separate from AD1/AD2 and absent in SRC-1/RAC3, explaining how the same molecule can coactivate at GREs yet corepress at AP-1 and NF-κB tethering elements; concurrently, SUMO-1 modification at K731/K788 in the NID was shown to modulate AR coactivation and subnuclear colocalization.\",\n      \"evidence\": \"Domain-mapping with Gal4 fusions, SUMO-site mutagenesis, confocal colocalization, reporter assays\",\n      \"pmids\": [\"12481024\", \"12060666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partner of the RD was unidentified\", \"Whether SUMOylation affects corepressor function was untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"TIF2 knockout mice revealed essential physiological roles: impaired spermiogenesis and placental development demonstrated reproductive requirements, while protection against obesity through altered PPARγ activity in WAT and facilitated SRC-1–PGC-1α interaction in BAT established TIF2 as a metabolic rheostat opposing SRC-1.\",\n      \"evidence\": \"TIF2−/− and SRC-1−/− mice, metabolic phenotyping, histology, protein interaction studies\",\n      \"pmids\": [\"12138202\", \"12507421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions (liver, muscle) not yet dissected\", \"Molecular targets in BAT thermogenesis beyond PGC-1α uncharacterized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether MOZ HAT activity or nucleosome recognition drove MOZ-TIF2 leukemogenesis was resolved: the C2HC nucleosome recognition motif (not HAT activity) of MOZ plus the TIF2 CBP-interaction domain were both required for transformation and AML induction in vivo.\",\n      \"evidence\": \"In vitro transformation assays, murine bone marrow transplant AML model, domain deletion mutagenesis\",\n      \"pmids\": [\"12676584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes of MOZ-TIF2 not identified\", \"Whether CBP depletion or gain-of-function acetylation is the critical mechanism was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"How GRIP1 protein levels are regulated was unknown; PKA was shown to induce GRIP1 ubiquitination and proteasome-mediated degradation, relocating it to proteasome-positive subnuclear foci and shortening its half-life.\",\n      \"evidence\": \"Pulse-chase, proteasome inhibitors, ts20 E1 cell line, ubiquitin co-IP, GFP-GRIP1 live imaging\",\n      \"pmids\": [\"15347661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ubiquitin ligase responsible was not identified\", \"Physiological contexts triggering PKA-mediated GRIP1 degradation were unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The binding partner of the GRIP1 repression domain was identified as IRF3, placing GRIP1 at the intersection of GR immunosuppression and TLR3-IRF3 innate immune signaling; GR and IRF3 compete for GRIP1 binding, providing a mechanistic basis for glucocorticoid suppression of antiviral responses.\",\n      \"evidence\": \"Yeast two-hybrid, endogenous co-IP in macrophages, GRIP1 KD/overexpression, KO mouse experiments\",\n      \"pmids\": [\"16362036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide scope of GRIP1-IRF3 target genes not mapped\", \"Whether other IRFs interact with GRIP1 RD was untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"MOZ-TIF2 was shown to act as a dominant inhibitor of CBP-dependent transcription by sequestering CBP away from PML bodies and reducing cellular CBP levels, with the CBP-binding domain required for extending bone marrow progenitor proliferative potential.\",\n      \"evidence\": \"Co-IP, FRET, reporter assays, bone marrow colony assays, immunofluorescence\",\n      \"pmids\": [\"15657427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CBP depletion is sufficient versus necessary for leukemogenesis was not fully resolved\", \"Direct chromatin targets of MOZ-TIF2–CBP complex not mapped genome-wide\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"SRC-2 was established as a critical regulator of hepatic glucose homeostasis: liver-specific knockout caused Von Gierke-like glycogenopathy through loss of RORα-dependent G6Pase expression, linking coactivator function to glucose production.\",\n      \"evidence\": \"Whole-body and liver-specific SRC-2 conditional KO mice, gene expression, coactivator functional assays with RORα\",\n      \"pmids\": [\"19039140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other RORα target genes require SRC-2 was not comprehensively assessed\", \"Mechanism of SRC-2 recruitment to RORα versus other NRs in liver not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"MOZ-TIF2 was shown to interact with PU.1 to activate CSF1R expression, and PU.1 was genetically required for AML stem cell establishment and maintenance, identifying the transcription factor partnership driving leukemia-initiating cell identity.\",\n      \"evidence\": \"Co-IP, PU.1 KO mouse, conditional suicide gene ablation, leukemia stem cell transplantation\",\n      \"pmids\": [\"20418886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MOZ-TIF2 directly acetylates PU.1 targets was not tested\", \"Additional cooperating mutations in AML progression not systematically catalogued\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Skeletal muscle-specific TIF2 ablation revealed antagonistic regulation of UCP3-mediated mitochondrial uncoupling by TIF2 and SRC-1, protecting against sedentariness-induced metabolic decline.\",\n      \"evidence\": \"Conditional skeletal muscle TIF2 KO mice, metabolic phenotyping, gene/protein expression\",\n      \"pmids\": [\"21035760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of TIF2 in myofibers beyond UCP3 not mapped\", \"Whether exercise modulates TIF2/SRC-1 balance was not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genome-wide and in vivo studies consolidated GRIP1's corepressor role: conditional macrophage GRIP1 KO caused increased LPS-induced shock, ChIP showed GRIP1 recruitment to p65-occupied NF-κB sites with GR, and transcriptomics revealed broad derepression of glucocorticoid-sensitive inflammatory genes, validating GRIP1 as the GR corepressor mediating anti-inflammatory glucocorticoid action.\",\n      \"evidence\": \"Conditional hematopoietic GRIP1 KO, ChIP-seq, transcriptome analysis, LPS challenge\",\n      \"pmids\": [\"22753499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GRIP1 RD interacts with additional repressive effectors beyond IRF3 at these sites was unknown\", \"GRIP1 contribution to other anti-inflammatory NR pathways (e.g., PPARγ) not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Glucocorticoid-induced, GR-dependent phosphorylation of GRIP1 was mapped to seven sites including CDK9-targeted residues, with phospho-GRIP1 recruited to native GR targets in a response element-specific manner, revealing that post-translational modification tunes GRIP1 activity at individual genomic loci.\",\n      \"evidence\": \"Mass spectrometry phosphosite identification, phosphospecific antibodies, ChIP, phospho-mutant assays\",\n      \"pmids\": [\"22158970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of each individual phosphosite was not fully dissected\", \"Whether phosphorylation affects corepressor function was untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"HEY1-NCOA2 fusion was identified as the defining genetic event of mesenchymal chondrosarcoma, establishing a second sarcoma-associated NCOA2 rearrangement beyond rhabdomyosarcoma fusions.\",\n      \"evidence\": \"Exon array profiling, RACE, RT-PCR, FISH across multiple mesenchymal chondrosarcoma cases\",\n      \"pmids\": [\"22034177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional mechanism of HEY1-NCOA2 in chondrosarcoma was not determined\", \"Whether the fusion acts through Notch pathway or NR coactivation was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"TIF2's N-terminal fragment was shown by HDX-MS to induce α-helical structure in the intrinsically disordered GR AF1 domain, establishing that TIF2 functions not merely as a scaffold but directly remodels receptor conformation to enable AF1-dependent transcription.\",\n      \"evidence\": \"HDX-MS, circular dichroism, mammalian two-hybrid, reporter assays\",\n      \"pmids\": [\"23132854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether conformational remodeling applies to other NR AF1 domains was untested\", \"High-resolution structure of TIF2–AF1 complex not obtained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Additional NCOA2 fusion partners (SRF, TEAD1, PAX3) were identified in infantile/congenital rhabdomyosarcoma; PAX3-NCOA2 was shown to enhance proliferation, motility, and G1/S progression while blocking myogenic differentiation, establishing NCOA2 as a recurrently rearranged oncogene in pediatric sarcomas.\",\n      \"evidence\": \"RNA-seq, FISH, RT-PCR for fusions; stable C2C12 lines with proliferation, migration, cell cycle, differentiation assays, nude mouse tumorigenesis\",\n      \"pmids\": [\"23463663\", \"24213582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets of PAX3-NCOA2 not mapped genome-wide\", \"Whether the NCOA2 coactivator domains are required for PAX3-NCOA2 transformation was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"SRC-2 was established as an essential coactivator of the BMAL1:CLOCK circadian heterodimer: genome-wide ChIP-seq showed extensive overlap with the BMAL1 cistrome, and SRC-2 KO disrupted circadian behavior, gene expression, and metabolome rhythmicity across tissues.\",\n      \"evidence\": \"SRC-2 KO mice, ChIP-seq, circadian behavior assays, metabolomics\",\n      \"pmids\": [\"24529706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRC-2 is rhythmically expressed or constitutively present at BMAL1 sites was not fully resolved\", \"Contribution of SRC-2 phosphorylation to circadian function untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"NCoA2 overexpression was shown to drive prostate neoplasia and, with PTEN loss, metastatic castration-resistant prostate cancer through hyperactivation of PI3K/AKT and MAPK; androgen deprivation upregulates NCoA2, creating a feedforward loop driving therapy resistance.\",\n      \"evidence\": \"Prostate-specific NCoA2 transgenic and Pten compound KO mice, signaling pathway analysis, human PCa sample validation\",\n      \"pmids\": [\"25295534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of NCoA2 in prostate cancer not comprehensively mapped\", \"Whether NCoA2 acts through AR or AR-independent mechanisms in CRPC was not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"SRC-2 was linked to cancer cell lipid metabolism: mTORC1-dependent phosphorylation activates SRC-2 to coactivate SREBP-1, driving glutamine-dependent de novo lipogenesis via reductive carboxylation in prostate cancer cells.\",\n      \"evidence\": \"Metabolic flux analysis, mTORC1 inhibition, SRC-2 KD/OE, murine tumor models, human tumor metabolic profiling\",\n      \"pmids\": [\"25664849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific mTORC1 phosphorylation sites on SRC-2 not mapped\", \"Whether this lipogenic axis operates in other cancer types was untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CDK9 was identified as the kinase phosphorylating GRIP1's N-terminal serine cluster within GR:GRIP1:CDK9 complexes, selectively potentiating coactivator but not corepressor function; phospho-GRIP1 and CDK9 were absent from GR transrepression sites, providing a mechanistic basis for GRE-specific functional diversification.\",\n      \"evidence\": \"Phosphospecific antibodies, co-IP, ChIP-seq, phospho-mutant analysis, kinase inhibition\",\n      \"pmids\": [\"29170386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases target different GRIP1 sites in the same complex was not resolved\", \"Structural basis of how phosphorylation switches GRIP1 from corepressor to coactivator mode unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ETV6-NCOA2 fusion was shown to form a transcriptional complex with wild-type ETV6 and p300, derepressing ETV6 targets; combined with Notch1 mutations it induces T/myeloid leukemia in both murine and human xenograft models, establishing a two-hit mechanism for this fusion leukemia.\",\n      \"evidence\": \"Co-IP of ETV6-NCOA2/ETV6/p300, bone marrow transplant models, human cord blood CD34+ xenografts, gene expression profiling\",\n      \"pmids\": [\"34624096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets of ETV6-NCOA2 not mapped genome-wide\", \"Whether the NCOA2 AD1 or AD2 domain is critical for ETV6-NCOA2 transformation was not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The HEY1-NCOA2 fusion mechanism was resolved: the fusion binds HEY1 target promoters and transactivates them (converting HEY1 repressor targets to activated ones), increases phospho-AKT, and drives proliferation through PDGFB/PDGFRA as direct targets.\",\n      \"evidence\": \"iPSC-derived MSCs with inducible HEY1-NCOA2, ChIP-seq, RNA-seq, phospho-protein analysis\",\n      \"pmids\": [\"35342947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether blocking PDGF signaling is therapeutically sufficient was not tested\", \"Epigenomic changes (histone marks) at HEY1-NCOA2 binding sites not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NCOA2 was established as a regulator of CD8+ T cell antitumor immunity: activation-induced CREB phosphorylation recruits NCOA2 to PGC-1α enhancers, driving mitochondrial biogenesis required for IFNγ production and tumor rejection; forced PGC-1α expression fully rescues NCOA2-deficient T cells.\",\n      \"evidence\": \"Conditional T-cell NCOA2 KO, ChIP at PGC-1α enhancer, metabolic analysis, adoptive transfer tumor models, PGC-1α rescue\",\n      \"pmids\": [\"37540802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NCOA2 regulates other metabolic programs in T cells beyond PGC-1α was not assessed\", \"Role in CD4+ T cell subsets or other immune lineages not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of GRIP1's dual coactivator/corepressor switching, the full catalog of E3 ligases controlling GRIP1 turnover, how tissue-specific post-translational modifications (phosphorylation, SUMOylation, palmitoylation) are coordinated to direct context-dependent function, and whether therapeutic targeting of specific NCOA2 fusion interfaces can selectively disrupt oncogenic programs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length NCOA2 or its repression domain\", \"E3 ubiquitin ligase for GRIP1 unidentified\", \"Systematic comparison of NCOA2 post-translational modifications across tissues not performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 14, 19, 24, 27, 28]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 5, 6, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 11, 37]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [37, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 19, 24, 27, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 19, 20, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 21, 27, 36]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 25, 29, 30, 33, 40]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 25, 34]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 13, 44]}\n    ],\n    \"complexes\": [\n      \"GR:GRIP1:CDK9 complex\",\n      \"BMAL1:CLOCK:SRC-2 complex\",\n      \"MOZ-TIF2:CBP complex\"\n    ],\n    \"partners\": [\n      \"CREBBP\",\n      \"NCOA1\",\n      \"NR3C1\",\n      \"ESR1\",\n      \"RORA\",\n      \"ARNTL\",\n      \"IRF3\",\n      \"CDK9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NCOA2 (TIF2/GRIP1/SRC-2) is a p160 family transcriptional coactivator that bridges liganded nuclear receptors to chromatin-modifying machinery, binding receptor AF-2 (and in some cases AF-1) activation functions through LxxLL NR-box motifs and recruiting secondary coactivators CBP/p300 via its AD1 domain and arginine methyltransferases CARM1/PRMT1 via AD2 [PMID:8670870, PMID:9742117, PMID:9430642, PMID:10381882]. Uniquely among p160 members, NCOA2 possesses an intrinsic repression domain that mediates GR transrepression at AP-1 and NF-κB tethering elements—a function critical for glucocorticoid anti-inflammatory signaling in macrophages—and its coactivator versus corepressor output is selectively governed by CDK9-mediated phosphorylation and regulated by SUMO-1 conjugation and PKA-triggered proteasomal degradation [PMID:12481024, PMID:22753499, PMID:29170386, PMID:12060666, PMID:15347661]. Beyond steroid receptor signaling, NCOA2 coactivates BMAL1:CLOCK to synchronize circadian gene expression, drives hepatic glucose production through RORα-dependent G6Pase transcription, controls energy homeostasis by antagonizing SRC-1/PGC-1α thermogenic programs, promotes CD8+ T cell mitochondrial fitness via PGC-1α upregulation, and regulates macrophage polarization through KLF4 coactivation [PMID:24529706, PMID:19039140, PMID:12507421, PMID:37540802, PMID:27464507]. Oncogenic NCOA2 fusions—MOZ-TIF2 in AML, HEY1-NCOA2 in mesenchymal chondrosarcoma, ETV6-NCOA2 in T-cell leukemia, and PAX3-NCOA2 in rhabdomyosarcoma—co-opt its CBP-recruiting AD1 domain or activation functions to drive aberrant transcription and signaling through PDGF/PI3K/AKT or HOX gene deregulation [PMID:12676584, PMID:35342947, PMID:34624096, PMID:24213582].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloning of TIF2/GRIP1 established that a dedicated 160 kDa nuclear protein mediates agonist- and AF-2-dependent coactivation of multiple nuclear receptors, resolving how NR ligand-binding domains transmit activation signals to the transcriptional machinery.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, and squelching assays in mammalian cells\",\n      \"pmids\": [\"8670870\", \"8643509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NR–TIF2 interaction undefined\", \"Downstream effector mechanism unknown\", \"Relative contribution versus other coactivators untested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of three LxxLL NR-box motifs as the minimal units for NR interaction explained how a single coactivator recognizes diverse receptor dimers, with individual boxes showing receptor-selective preferences and cooperative binding enabling allosteric communication within heterodimers.\",\n      \"evidence\": \"NR-box mutagenesis combined with yeast two-hybrid and GST pulldown across multiple NR pairs\",\n      \"pmids\": [\"9742117\", \"9111344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of NR-box in complex with LBD\", \"Auxiliary interaction domains not yet mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Functional dissection of AD1 and AD2 output domains revealed that NCOA2 activates transcription through two separable mechanisms—CBP/p300 recruitment (AD1) and a CBP-independent pathway (AD2)—establishing NCOA2 as a scaffold that integrates multiple chromatin-modifying activities.\",\n      \"evidence\": \"Mutagenesis separating AD1-CBP interaction from AD2, dominant-negative NID peptide in mammalian reporter assays\",\n      \"pmids\": [\"9430642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"AD2 effector unidentified\", \"Relative contributions of AD1 versus AD2 at native genes unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery of CARM1 as the AD2-recruited arginine methyltransferase completed the mechanistic picture of both NCOA2 output arms, demonstrating that NCOA2 couples NR activation to histone H3 arginine methylation via its C-terminal domain.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro methyltransferase reconstitution, CARM1 SAM-binding mutant abolishing coactivation\",\n      \"pmids\": [\"10381882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo ChIP confirmation at native loci not yet performed\", \"Specificity of CARM1 histone substrate in NR-regulated chromatin unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapping of an auxiliary NID (NIDaux) and demonstration that NCOA2 binds both NR AF-1 and AF-2 domains established that NCOA2 possesses dual signal-input surfaces, enabling it to bridge N- and C-terminal receptor activation domains for synergistic transcription.\",\n      \"evidence\": \"Deletion and point mutagenesis with GST pulldown and mammalian two-hybrid for GR, AR, and other NRs\",\n      \"pmids\": [\"9920895\", \"10454563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AF-1 binding unresolved\", \"Whether bridging occurs simultaneously in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"ChIP-based recruitment of GRIP1 to GR-repressed AP-1 elements overturned the assumption that p160 proteins are exclusively coactivators, revealing that NCOA2 can function as a GR corepressor at tethering GREs—a property later mapped to a unique repression domain absent from SRC-1 and SRC-3.\",\n      \"evidence\": \"ChIP at collagenase-3 promoter in U2OS cells, dominant-negative GRIP1 fragments, Gal4-tethered repression domain mapping\",\n      \"pmids\": [\"11689447\", \"12481024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of downstream repression effectors unknown\", \"Whether the repression domain recruits HDACs or other factors untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout mouse studies established non-redundant physiological roles for NCOA2: male fertility (Sertoli cell function), female fertility (decidual placentation), energy homeostasis (antagonism of SRC-1/PGC-1α thermogenic axis), and adrenocortical steroidogenesis, distinguishing NCOA2 from other p160 members in vivo.\",\n      \"evidence\": \"Global TIF2-knockout mice with histological, metabolic, and reproductive phenotyping; compound SRC-1/TIF2 double knockouts\",\n      \"pmids\": [\"12138202\", \"12507421\", \"15070739\", \"17135362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions not dissected with conditional alleles at this stage\", \"Downstream target genes mediating each phenotype largely unidentified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of SUMO-1 conjugation at K239/K731/K788 and its requirement for AR-dependent coactivation and nuclear colocalization introduced post-translational regulation as a layer controlling NCOA2 function, later complemented by discovery of PKA-triggered ubiquitin-proteasomal degradation.\",\n      \"evidence\": \"Site-directed mutagenesis of SUMO sites with confocal microscopy and reporter assays; pulse-chase and ubiquitin co-IP with proteasome inhibitors\",\n      \"pmids\": [\"12060666\", \"15347661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase(s) responsible not identified\", \"Interplay between sumoylation and ubiquitination unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The crystal structure of the GR LBD–dexamethasone–TIF2 NR-box peptide complex provided the first atomic view of LxxLL-motif recognition by a steroid receptor, revealing charge-clamp contacts and a novel GR dimerization interface.\",\n      \"evidence\": \"X-ray crystallography at atomic resolution with functional validation of dimer interface mutations\",\n      \"pmids\": [\"12151000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length NCOA2 structure unavailable\", \"How auxiliary NID and AF-1 binding surfaces are spatially arranged relative to the LxxLL-clamp unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that the MOZ-TIF2 fusion causes AML in mice and requires both the MOZ nucleosome-recognition motif and the TIF2 CBP-interaction domain for transformation established the mechanistic paradigm for NCOA2-containing oncogenic fusions: aberrant chromatin targeting coupled to CBP sequestration.\",\n      \"evidence\": \"Murine bone marrow transplantation with domain-deletion mutants of MOZ-TIF2\",\n      \"pmids\": [\"12676584\", \"15657427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of MOZ-TIF2 not yet genome-widely mapped\", \"Whether CBP sequestration alone suffices or additional MOZ targets contribute unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Liver-specific SRC-2 ablation producing a glycogen storage disease phenotype through loss of RORα-dependent G6Pase expression placed NCOA2 as a central regulator of hepatic glucose homeostasis, expanding its physiological scope beyond reproduction and thermogenesis.\",\n      \"evidence\": \"Whole-body and liver-specific conditional knockout mice with glucose metabolism phenotyping and RORα coactivation reporter assays\",\n      \"pmids\": [\"19039140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other RORα target genes contribute to the phenotype untested\", \"Redundancy with SRC-1/SRC-3 in liver not fully explored\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Conditional macrophage-specific deletion proved GRIP1 is essential for GR-mediated repression of NF-κB targets in vivo, with GRIP1-deficient mice hypersensitive to LPS shock, definitively establishing NCOA2's corepressor function as physiologically critical for glucocorticoid anti-inflammatory action.\",\n      \"evidence\": \"Hematopoietic-cell-restricted Cre-lox knockout, genome-wide RNA-seq, LPS endotoxemia model\",\n      \"pmids\": [\"22753499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific genes drive lethality not pinpointed\", \"Whether pharmacological GR ligands can bypass GRIP1 requirement untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genome-wide ChIP-seq showing diurnal NCOA2 recruitment overlapping the BMAL1 cistrome, combined with behavioral and metabolomic disruption in knockout mice, established NCOA2 as a core circadian coactivator linking clock transcription to peripheral metabolite rhythmicity.\",\n      \"evidence\": \"ChIP-seq for SRC-2 across circadian cycle, wheel-running behavioral assays, hepatic metabolomics in SRC-2 KO mice\",\n      \"pmids\": [\"24529706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NCOA2 acetylation or phosphorylation oscillates with clock phase unknown\", \"Relative contribution versus other BMAL1 coactivators not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that CDK9 phosphorylates GRIP1 within GR:GRIP1:CDK9 complexes and that phospho-GRIP1 selectively potentiates coactivator but not corepressor functions explained how a single cofactor can perform opposite transcriptional roles at different GR target genes, resolving a long-standing mechanistic paradox.\",\n      \"evidence\": \"Co-IP of ternary complex, phosphospecific antibodies, ChIP-seq at GR-activated versus GR-repressed loci, phosphosite mutagenesis in macrophages\",\n      \"pmids\": [\"29170386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CDK9 recruitment mechanism to the complex unresolved\", \"Whether other kinases contribute at different gene sets untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genome-wide characterization of the HEY1-NCOA2 fusion demonstrated it converts HEY1 from a repressor to a transactivator at promoter-proximal sites, activating PDGFB/PDGFRA and PI3K/AKT signaling, providing the first mechanistic rationale for targeted therapy in mesenchymal chondrosarcoma.\",\n      \"evidence\": \"ChIP-seq and RNA-seq in iPSC-derived mesenchymal stem cells expressing inducible HEY1-NCOA2, phospho-AKT readouts\",\n      \"pmids\": [\"35342947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tumor model with fusion expression not reported\", \"Whether PI3K/AKT inhibition is curative or only cytostatic unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Conditional T-cell-specific knockout revealed that NCOA2 sustains CD8+ T cell antitumor immunity by driving PGC-1α-dependent mitochondrial biogenesis, with rescue experiments confirming the NCOA2→PGC-1α axis as the critical pathway, expanding NCOA2 function into adaptive immunity.\",\n      \"evidence\": \"Ncoa2fl/fl/CD4Cre mice, ChIP showing NCOA2 at PGC-1α enhancers, MC38 tumor model, PGC-1α rescue of mitochondrial function\",\n      \"pmids\": [\"37540802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NCOA2 regulates CD4+ T cell or other lymphocyte subsets similarly untested\", \"Upstream signals besides CREB phosphorylation not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structural model of NCOA2, the identity of direct enzymatic targets of the repression domain, and the basis for gene-specific phospho-isoform deployment remain major unresolved questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length cryo-EM or X-ray structure exists\", \"Repression domain effector mechanism unknown\", \"Phospho-isoform determinants at individual genomic loci not decoded\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8, 10, 11, 13, 30, 41, 45, 50]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 8, 10, 11, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 16, 17]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [17, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8, 10, 11, 13, 30, 41, 45, 50]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [40, 42, 49]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 37, 45, 50]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 30, 32, 42]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 39]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [41]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 18, 31, 34, 38, 40, 48, 49]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"complexes\": [\n      \"p160/NR coactivator complex\",\n      \"GR:GRIP1:CDK9 complex\",\n      \"MOZ-TIF2/BRPF1 complex\"\n    ],\n    \"partners\": [\n      \"CBP\",\n      \"CARM1\",\n      \"NR3C1\",\n      \"ESR1\",\n      \"BMAL1\",\n      \"KLF4\",\n      \"CTNNB1\",\n      \"PPARG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}