{"gene":"NCOA3","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"AIB1 (NCOA3) protein interacts with estrogen receptors in a ligand-dependent fashion and enhances estrogen-dependent transcription when transfected into cells.","method":"Co-immunoprecipitation, transfection/reporter assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand-dependent interaction demonstrated by co-IP and functional transactivation assay, independently replicated across multiple labs in subsequent studies","pmids":["9252329"],"is_preprint":false},{"year":1997,"finding":"ACTR (NCOA3) is a histone acetyltransferase that directly binds nuclear receptors in a hormone-dependent manner and recruits CBP and P/CAF to form a multisubunit coactivator complex containing at least three classes of histone acetyltransferases.","method":"In vitro HAT assay with purified ACTR, co-immunoprecipitation, direct binding assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified protein, plus reciprocal co-IP for complex formation; foundational biochemical study","pmids":["9267036"],"is_preprint":false},{"year":1997,"finding":"p/CIP (NCOA3) is present in cells as a complex with CBP and is required for transcriptional activity of nuclear receptors and CBP/p300-dependent transcription factors; leucine-rich charged helical interaction motifs in p/CIP are required for receptor-specific gene activation.","method":"Co-immunoprecipitation, transfection/reporter assay, deletion mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical complex identification by co-IP, functional validation by mutagenesis and reporter assay, replicated by independent labs","pmids":["9192892"],"is_preprint":false},{"year":1997,"finding":"TRAM-1 (NCOA3) binds thyroid hormone receptor and other nuclear receptors in a ligand-dependent manner via a region outside the AF-2 domain (including helix 3 of the ligand binding domain), distinct from SRC-1 binding.","method":"Far-Western expression screening, GST pulldown, transfection/reporter assay, AF-2 and helix-3 mutant TR binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — far-Western cloning, direct binding assays with LBD mutants, and functional transactivation assays in a single rigorous study","pmids":["9346901"],"is_preprint":false},{"year":2000,"finding":"AIB1 (NCOA3) is a phosphoprotein that is phosphorylated in vitro and in vivo by MAPK; MAPK phosphorylation of AIB1 enhances its transcriptional activity and stimulates recruitment of p300 and associated histone acetyltransferase activity, providing a mechanism for growth factor modulation of estrogen action.","method":"In vitro kinase assay, in vivo phosphorylation analysis, co-immunoprecipitation, reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with purified MAPK plus in vivo phosphorylation and functional co-IP in same study","pmids":["10866661"],"is_preprint":false},{"year":2000,"finding":"Endogenous AIB1 and estrogen receptor form a ligand-specific complex in MCF-7 breast cancer cells detectable by immunoprecipitation; complex formation is observed with estradiol but much less with the partial agonist monohydroxytamoxifen. In vitro binding affinity of mouse ER for AIB1 is ~40–120 nM.","method":"Immunoprecipitation of endogenous proteins, in vitro binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP in intact cells plus quantitative in vitro binding, demonstrating physiological relevance","pmids":["11050174"],"is_preprint":false},{"year":2000,"finding":"SRC-3/NCOA3 knockout mice exhibit dwarfism, delayed puberty, reduced female reproductive function, and blunted mammary gland development, demonstrating in vivo roles in the growth hormone regulatory pathway and estrogen production.","method":"Genetic knockout mouse model with hormonal and phenotypic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with pleiotropic phenotypic readouts and hormonal analysis, replicated/confirmed across multiple studies","pmids":["10823921"],"is_preprint":false},{"year":2000,"finding":"TRAM-1 (NCOA3) acts as an androgen receptor (AR) coactivator: it binds the AR ligand-binding domain and the N-terminal/DNA-binding domains in a ligand-dependent manner and enhances DHT-dependent AR transactivation ~5-fold in cell-based assays.","method":"Yeast two-hybrid, GST affinity matrix binding assay, transfection/reporter assay, immunohistochemistry","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro GST pulldown and functional transactivation in mammalian cells, single lab","pmids":["10965917"],"is_preprint":false},{"year":2002,"finding":"SRC-3 (NCOA3) associates with the IκB kinase (IKK) complex (but not SRC-1), is phosphorylated by IKK in vitro, and undergoes TNFα-induced phosphorylation and translocation from cytoplasm to nucleus in cells; SRC-3 enhances NF-κB-mediated gene expression in concert with IKK.","method":"Biochemical purification of SRC-3 protein complexes, mass spectrometry identification, in vitro kinase assay, subcellular fractionation/immunofluorescence, reporter assay, SRC-3 null mouse gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical purification with MS identification, in vitro kinase assay, cellular localization experiment, and genetic evidence from knockout mice","pmids":["11971985"],"is_preprint":false},{"year":2002,"finding":"p/CIP (NCOA3) is predominantly cytoplasmic in many cell types; nuclear import and export are regulated by an N-terminal nuclear import signal and C-terminal leucine-rich CRM1-dependent nuclear export sequences; cytoplasmic shuttling is cell cycle-dependent (S and late M phases) and requires an intact microtubule network; only nuclear p/CIP complexes possess histone acetyltransferase activity.","method":"Immunofluorescence, live cell imaging with GFP fusions, leptomycin B treatment, immunoaffinity purification with HAT assay, deletion/point mutagenesis, fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal localization methods, functional consequence (HAT activity linked to compartment), mutagenesis confirming export sequences","pmids":["12192059"],"is_preprint":false},{"year":2003,"finding":"p/CIP (NCOA3) recruits GCN5 histone acetyltransferase via its AD1 activation domain to facilitate RARα-dependent transcription; two helical motifs within AD1 are required for interactions with both GCN5 and CBP.","method":"Yeast genetic screen (SAGA component mutants), co-immunoprecipitation, siRNA knockdown, reporter assay, deletion and point mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast epistasis combined with mammalian co-IP, siRNA, reporter assays, and mutagenesis in one study","pmids":["12885766"],"is_preprint":false},{"year":2004,"finding":"ACTR/NCOA3 directly interacts with E2F1 through its N-terminal domain and is recruited to E2F target gene promoters, stimulating transcription of G1/S transition genes independently of estrogen receptor, thereby promoting breast cancer cell proliferation and antiestrogen resistance.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, adenoviral RNAi, reporter assay, cell proliferation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ChIP, functional RNAi knockdown with specific proliferation phenotype, multiple orthogonal methods in single study","pmids":["15169882"],"is_preprint":false},{"year":2004,"finding":"AIB1 coactivator uniquely mediates agonist-induced (but not antagonist-induced) ERα degradation via the ubiquitin-proteasome machinery; AIB1 recruitment by ERα is both necessary and sufficient to promote ERα degradation and is required for RNA polymerase II recruitment to ERα target promoters.","method":"RNAi knockdown, chromatin immunoprecipitation, reporter assay, Western blot for ERα stability","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts (ER stability, PolII recruitment, target gene transcription) in one study","pmids":["15289619"],"is_preprint":false},{"year":2004,"finding":"AIB1 overexpression in transgenic mice leads to increased mammary IGF-I mRNA and serum IGF-I protein, with activation of IGF-I receptor and downstream PI3K/AKT signaling in mammary epithelial cells; AIB1 knockdown in tumor cells reduces IGF-I mRNA and increases apoptosis, demonstrating an autocrine IGF-I loop as the oncogenic mechanism.","method":"Transgenic mouse model, siRNA knockdown, signaling pathway analysis (Western blot for IGF-IR, PI3K/AKT), apoptosis assay","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic gain-of-function plus RNAi loss-of-function with defined molecular pathway, replicated across mouse and cell models","pmids":["15380517"],"is_preprint":false},{"year":2004,"finding":"AIB1 deficiency in AIB1(-/-)/v-Ha-ras mice causes partial resistance to IGF-I signaling due to significant reduction in insulin receptor substrates, suppressing mammary tumorigenesis and metastasis by inhibiting cell proliferation and migration.","method":"Genetic knockout in mammary tumor model, IGF-I signaling pathway analysis, tumor incidence assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout genetic model with defined molecular pathway (IRS reduction) and functional phenotype (tumor suppression)","pmids":["14996752"],"is_preprint":false},{"year":2004,"finding":"p/CIP (NCOA3) acts as a positive regulator of STAT6 transcriptional activation by indirectly interacting with STAT6 via p300/CBP; overexpression of the CBP-interacting domain of p/CIP blocks STAT6-mediated transactivation and CD23 expression in IL-4-stimulated B cells. ChIP demonstrates IL-4-induced recruitment of p/CIP to the IgH germ-line ε promoter.","method":"Co-immunoprecipitation, reporter assay, chromatin immunoprecipitation, overexpression/dominant-negative approach","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and reporter assay in single lab; STAT6 interaction is indirect (via p300)","pmids":["15145939"],"is_preprint":false},{"year":2006,"finding":"SRC-3/AIB1 (NCOA3) is degraded by the REGγ proteasome in a ubiquitin- and ATP-independent manner; REGγ directly interacts with SRC-3 and promotes its degradation by the 20S proteasome, as demonstrated by in vitro reconstitution with purified REGγ, SRC-3, and 20S proteasome.","method":"In vitro proteasome proteolysis assay with purified components, RNAi knockdown and overexpression, reporter assay for ER target gene expression","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins plus cellular gain/loss-of-function experiments with functional readouts","pmids":["16439211"],"is_preprint":false},{"year":2006,"finding":"AIB1 (NCOA3) is sumoylated, and sumoylation attenuates its transactivation activity; estrogen treatment leads to increased phosphorylation and decreased sumoylation of AIB1; sumoylation and phosphorylation coordinately regulate AIB1 transcriptional output.","method":"In vivo sumoylation assay, phosphorylation analysis, reporter assay, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo sumoylation and phosphorylation analyses with reporter assay, single lab, two methods","pmids":["16760465"],"is_preprint":false},{"year":2006,"finding":"SRC-3/NCOA3 is phosphorylated by p38MAPK during retinoic acid (RA)-dependent RARα activation; this phosphorylation first facilitates RARα target gene activation by controlling the dynamics of SRC-3/RARα interactions, then promotes SRC-3 degradation to inhibit transcription; phosphorylation and degradation occur specifically within the context of RARα complexes.","method":"In vitro kinase assay, p38MAPK inhibitor treatment, Western blot, reporter assay, protein stability assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus specific inhibitor and functional reporter assay, single lab","pmids":["16456540"],"is_preprint":false},{"year":2006,"finding":"CARM1 methylates p/CIP (NCOA3) at three conserved arginine residues in a glutamine-rich C-terminal region; CARM1 is the required methyltransferase (not other PRMTs); methylation increases p/CIP turnover by enhanced degradation and impairs p/CIP association with CBP, thereby negatively impacting transcription.","method":"In vitro methylation assay, metabolic labeling, mass spectrometry identification of methylation sites, CARM1 knockout MEF extracts, CBP co-immunoprecipitation, methylation site mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, MS site identification, genetic knockout validation, and functional co-IP, multiple orthogonal methods","pmids":["17043108"],"is_preprint":false},{"year":2008,"finding":"SRC-3/AIB1 is phosphorylated at C-terminal tyrosine Y1357 by c-Abl kinase; this phosphorylation is induced by IGF-I, EGF, and estrogen and is required for AIB1 coactivation of ERα, PR-B, NF-κB, and AP-1 promoters; Y1357 phosphorylation modulates AIB1 association with c-Abl, ERα, p300, and CARM1.","method":"In vitro kinase assay, phospho-specific antibody, co-immunoprecipitation, reporter assay, imatinib inhibitor treatment, cell growth and focus formation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with specific kinase plus phospho-site mutagenesis, co-IP, and functional reporter/phenotypic assays in one study","pmids":["18765637"],"is_preprint":false},{"year":2008,"finding":"SRC-3/AIB1 is required for focal adhesion turnover, focal adhesion kinase activation, and directly regulates transcription of MMP-2 and MMP-13 through coactivation of AP-1 and PEA3, promoting prostate cancer cell migration and invasion.","method":"siRNA knockdown, focal adhesion turnover assay, chromatin immunoprecipitation, reporter assay, invasion assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined molecular pathway (focal adhesion kinase, ChIP for MMP promoters), single lab","pmids":["18593949"],"is_preprint":false},{"year":2008,"finding":"AIB1 serves as a PEA3 coactivator and forms complexes with PEA3 on MMP2 and MMP9 promoters to enhance their expression in breast cancer cells; AIB1 deficiency reduces lung metastasis in the PyMT mouse model and AIB1-null tumor cells maintain epithelial markers and form polarized acinar structures unlike wild-type tumor cells.","method":"Knockout mouse/tumor transplantation model, chromatin immunoprecipitation, reporter assay, 3D culture, invasion assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model plus ChIP at defined promoters plus cell biology assays, multiple orthogonal methods","pmids":["18644862"],"is_preprint":false},{"year":2008,"finding":"ACTR/AIB1 (NCOA3) binds NCBD domain of CBP/p300 through mutual synergistic folding; the free ACTR activation domain (residues 1041-1088) is completely unfolded in isolation but forms a well-ordered helical complex upon binding to CBP; backbone dynamics of the complex are consistent with a fully folded protein.","method":"NMR relaxation (15N longitudinal/transverse rates, heteronuclear NOE), secondary chemical shift analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous NMR structural and dynamic characterization; defines mechanism of coupled folding-binding","pmids":["18177052"],"is_preprint":false},{"year":2008,"finding":"PP1, PP2A, and PDXP are key negative regulators of SRC-3/AIB1 coactivator activity; PDXP and PP2A dephosphorylate SRC-3 and inhibit its ligand-dependent association with estrogen receptor; PP1 stabilizes SRC-3 by dephosphorylating a phospho-degron at Ser101/Ser102, preventing proteasome-dependent turnover; PP1 regulates SRC-3-dependent cell proliferation and invasion in breast cancer cells.","method":"Functional genomic phosphatase screen, in vitro dephosphorylation assay, co-immunoprecipitation, SRC-3 stability assay, cell proliferation and invasion assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-scale functional screen followed by biochemical validation (in vitro dephosphorylation), site identification, and cellular phenotypic assays","pmids":["18922467"],"is_preprint":false},{"year":2010,"finding":"SRC3/AIB1 (NCOA3) interacts with hormone-activated androgen receptor via synergistic binding of its first and third LXXLL motifs; crystal structure reveals the molecular basis for AR's preference for SRC3 over other coactivators; AR mutations found in prostate cancer patients correlate with their SRC3 binding potency.","method":"Crystal structure determination, mutagenesis, biochemical binding assays, functional transactivation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis and biochemical/functional validation in one rigorous study","pmids":["20086010"],"is_preprint":false},{"year":2010,"finding":"ATBF1 inhibits estrogen receptor function by selectively competing with AIB1 but not GRIP1 or SRC-1 for binding to ERα; ATBF1 physically interacts with ER via multiple domains in both proteins and inhibits ER-mediated gene transcription and cell growth.","method":"In vitro and in vivo co-immunoprecipitation, competitive binding assay, reporter assay, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo co-IP with functional reporter and cell growth assays, single lab","pmids":["20720010"],"is_preprint":false},{"year":2010,"finding":"NCOA3 (SRC-3) promotes Ago2 expression at the transcriptional level in hippocampal neurons, thereby stimulating miRNA function; Ncoa3 knockdown reduces dendritic complexity and dendritic spine maturation in a miRNA-dependent manner that can be rescued by Ago2 overexpression.","method":"RNAi knockdown, Ago2 overexpression rescue, fluorescence microscopy for dendritic morphology, reporter assays for miRNA function","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with specific rescue, two orthogonal readouts (Ago2 expression, dendritic morphology), single lab","pmids":["26105073"],"is_preprint":false},{"year":2011,"finding":"AIB1 (NCOA3) is phosphorylated at Ser728 and Ser867 by CDK1/Cyclin B at the onset of mitosis; this phosphorylation correlates with exclusion of AIB1 from condensed chromatin and redistribution to the cell periphery without affecting its transcriptional properties; PP1 likely mediates dephosphorylation at mitotic exit.","method":"In vitro kinase assay, specific kinase inhibitors, phospho-specific antibody, Western blot, fluorescence microscopy, subcellular fractionation, luciferase reporter assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus phospho-site mutagenesis, subcellular fractionation with fluorescence microscopy, and functional reporter assay in one study","pmids":["22163316"],"is_preprint":false},{"year":2012,"finding":"Ncoa3 interacts with the orphan nuclear receptor Esrrb via its ligand-binding domain and bridges Esrrb to RNA polymerase II complexes; Ncoa3 is required for induction and maintenance of pluripotency in embryonic stem cells and shares genome-wide gene regulatory functions with Esrrb at active enhancers through cooperation with the Oct4-Sox2-Nanog circuitry.","method":"Co-immunoprecipitation, ChIP-sequencing, microarray gene expression analysis, RNAi knockdown, ESC self-renewal and differentiation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP-seq genome-wide mapping, microarray, and functional knockdown with pluripotency readouts, multiple orthogonal methods","pmids":["23019124"],"is_preprint":false},{"year":2012,"finding":"Ncoa3 binds the Nanog promoter and recruits CBP (histone acetyltransferase) and CARM1 (histone arginine methyltransferase) to activate Nanog expression in mouse ESCs; GSK3 signaling downregulates Ncoa3 protein level to suppress Nanog expression.","method":"Chromatin immunoprecipitation, co-immunoprecipitation, RNAi knockdown, reporter assay, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP with functional knockdown readouts, single lab","pmids":["22977234"],"is_preprint":false},{"year":2012,"finding":"PIAS1 is the SUMO E3 ligase responsible for AIB1 sumoylation; PIAS1 co-immunoprecipitates with AIB1, and overexpression of wild-type PIAS1 (but not the E3 ligase-dead C350S mutant) increases AIB1 sumoylation, promotes AIB1 stability, represses AIB1 transcriptional activity, and attenuates AIB1 interaction with ERα, reducing cell growth.","method":"Co-immunoprecipitation, sumoylation assay, reporter assay, PIAS1 E3 ligase mutant, cell proliferation assay","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with E3 ligase mutant validation and functional reporter assay, single lab","pmids":["22283414"],"is_preprint":false},{"year":2012,"finding":"p/CIP (NCOA3) and SRC-1 cooperatively regulate insulin signaling through IRS1: deletion of both coactivators significantly increases IRS1 expression in fat and muscle cells and in vivo, enhancing insulin sensitivity and glucose metabolism.","method":"Double knockout mouse model, gene expression analysis, glucose uptake assay, insulin sensitivity testing","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-knockout model with specific IRS1 molecular readout and metabolic phenotype, single lab","pmids":["22859932"],"is_preprint":false},{"year":2013,"finding":"PTEN interacts with AIB1 via its phosphatase domain and acts as a bridge between AIB1 and the E3 ubiquitin ligase Fbw7α (via PTEN's C2 domain), promoting ubiquitin-mediated degradation of AIB1 in a phosphatase-activity-independent manner, thereby reducing AIB1 transcriptional activity.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, PTEN phosphatase mutant, cell proliferation assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying bridge mechanism, phosphatase-dead mutant, functional knockdown, single lab","pmids":["23514585"],"is_preprint":false},{"year":2013,"finding":"AIB1 cooperates with ERα to promote EMT in breast cancer cells through activation of SNAI1 transcription; AIB1-ERα complex binds ERα-binding sites on the SNAI1 promoter to upregulate SNAI1, which represses E-cadherin expression; this requires an ERα-binding site on SNAI1 promoter.","method":"Overexpression and knockdown of AIB1 and SNAI1, E-cadherin expression analysis, migration/invasion assay, promoter analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with defined promoter dependence and multiple phenotypic readouts, single lab","pmids":["23762395"],"is_preprint":false},{"year":2014,"finding":"NCOA3 regulates MUC4 promoter accessibility (chromatin remodeling) as demonstrated by micrococcal nuclease digestion and ChIP assays; NCOA3 knockdown abrogates retinoic acid-mediated MUC4 upregulation; NCOA3 also stabilizes mucins (MUC4 and MUC1) post-translationally through fucosylation via FUT8.","method":"Chromatin immunoprecipitation, micrococcal nuclease digestion assay, siRNA knockdown, gene expression analysis, FUT8 knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and nuclease accessibility assay plus FUT8 knockdown validation, single lab","pmids":["25531332"],"is_preprint":false},{"year":2016,"finding":"NCOA3 is a transcriptional target of XBP1; NCOA3 is required for optimal activation of the PERK-eIF2α-ATF4 pathway during UPR; NCOA3 is required for XBP1 induction during estrogen stimulation, forming a positive feedback loop maintaining high NCOA3 and XBP1 levels in breast cancer cells.","method":"RNAi knockdown, reporter assay, Western blot for UPR pathway components, promoter analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined pathway readouts (PERK-ATF4 activation), reporter assay for XBP1-NCOA3 feedback, single lab","pmids":["27109102"],"is_preprint":false},{"year":2018,"finding":"MAD2L2 (REV7) interacts with NCOA3, and MAD2L2 overexpression suppresses NCOA3 by activating p38 kinase, which phosphorylates NCOA3 and leads to its ubiquitination and proteasomal degradation.","method":"Immunoprecipitation/mass spectrometry, co-immunoprecipitation, p38 inhibitor, Western blot for NCOA3 stability, ubiquitination assay, in vitro and in vivo tumor models","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus biochemical validation of mechanism (p38-dependent phosphorylation leading to ubiquitination), single lab","pmids":["29360267"],"is_preprint":false},{"year":2018,"finding":"Cytoplasmic PELP1 forms a complex with AIB1 (NCOA3), elevates AIB1 phosphorylation at Thr24, and promotes cancer stem cell-like (ALDH+) tumorsphere formation; direct manipulation of AIB1 levels or pharmacological inhibition of AIB1 abrogates cytoplasmic PELP1-induced tumorsphere formation.","method":"Co-immunoprecipitation, phospho-specific Western blot, shRNA knockdown, tumorsphere/ALDH assay, AIB1 inhibitor (SI-2), syngeneic in vivo tumor model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus shRNA and pharmacological inhibition with specific phenotypic readout, single lab","pmids":["29348189"],"is_preprint":false},{"year":2009,"finding":"CK1δ phosphorylates AIB1 at a novel site (S601) and ERα in vitro; CK1δ interacts with ERα and AIB1 in vivo and increases ERα-AIB1 association; CK1δ overexpression promotes AIB1 protein stability in an estradiol-dependent manner; CK1δ silencing reduces ERα transcriptional activity and decreases AIB1 levels via proteasome-mediated degradation.","method":"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, proteasome inhibitor treatment, Western blot","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus cellular co-IP and functional reporter assay, single lab","pmids":["19339517"],"is_preprint":false},{"year":2021,"finding":"SRC-3 (NCOA3) is enriched in regulatory T cells (Tregs) in mice and humans; SRC-3 depletion or pharmacological inhibition causes failure of Treg induction from resting T cells and loss of ability to suppress proliferation of stimulated T cells.","method":"Bioinformatics analysis of public data, directed cellular assays, pharmacological inhibition, T cell suppression assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bioinformatics plus cellular loss-of-function with specific Treg functional readouts, single lab","pmids":["33564037"],"is_preprint":false},{"year":2009,"finding":"AIB1 directly interacts with ERRα as demonstrated by FRET, mammalian two-hybrid, and co-immunoprecipitation of endogenous proteins; AIB1 enhances ERRα transcriptional activity in ERα-negative breast cancer cell lines; both proteins are recruited to ERRα target gene promoters; blocking ERRα with an inverse agonist abolishes AIB1-ERRα interaction and coactivation.","method":"FRET, mammalian two-hybrid, endogenous co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, inverse agonist treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent interaction assays (FRET, two-hybrid, endogenous co-IP) plus ChIP and functional reporter, single lab but highly rigorous","pmids":["19491275"],"is_preprint":false}],"current_model":"NCOA3 (AIB1/SRC-3/ACTR) is a multifunctional transcriptional coactivator that binds ligand-activated nuclear receptors (ER, AR, TR, RARα, ERRα, Esrrb, and others) and non-receptor transcription factors (E2F1, NF-κB, AP-1, PEA3, STAT6) to recruit histone-modifying enzymes (CBP/p300, P/CAF, GCN5, CARM1) and chromatin-remodeling machinery; its activity and stability are tightly regulated by multiple post-translational modifications including phosphorylation by MAPK, IKK, p38MAPK, CDK1/CyclinB, CK1δ, c-Abl, and dephosphorylation by PP1/PP2A/PDXP, sumoylation by PIAS1, arginine methylation by CARM1, and ubiquitin-mediated degradation via the REGγ/20S proteasome or Fbw7α E3 ligase; subcellular localization is regulated by microtubule-dependent nuclear-cytoplasmic shuttling and cell-cycle-dependent chromatin exclusion (via CDK1 phosphorylation at mitosis); in vivo, NCOA3 is required for normal growth, female reproduction, mammary gland development, placentation, ESC pluripotency, and Treg function, and its oncogenic overexpression drives breast and other cancers through IGF-I/PI3K/AKT autocrine signaling, MMP-mediated invasion, E2F1-dependent cell cycle progression, and UPR pathway activation."},"narrative":{"mechanistic_narrative":"NCOA3 (AIB1/SRC-3/ACTR/p/CIP/TRAM-1) is a multifunctional transcriptional coactivator that couples ligand-activated nuclear receptors to chromatin-modifying machinery to drive hormone-dependent gene expression, growth, and oncogenesis [PMID:9252329, PMID:9267036]. It binds nuclear receptors including estrogen receptor, thyroid hormone receptor, androgen receptor, and ERRα in a ligand-dependent manner through LXXLL/helical interaction motifs, with crystallographic and binding data defining receptor selectivity [PMID:9252329, PMID:9346901, PMID:10965917, PMID:20086010, PMID:19491275]. Bound to receptors and to non-receptor factors such as E2F1, NF-κB, AP-1, PEA3, and STAT6, NCOA3 functions as an intrinsic histone acetyltransferase and as an assembly platform that recruits CBP/p300, P/CAF, and GCN5 acetyltransferases and the arginine methyltransferase CARM1 to target promoters [PMID:9267036, PMID:12885766, PMID:15169882, PMID:15145939, PMID:18593949]; its activation domain is intrinsically disordered and folds upon binding the NCBD of CBP/p300 [PMID:18177052]. NCOA3 activity and abundance are governed by an extensive post-translational network: activating phosphorylation by MAPK, IKK, c-Abl, CK1δ, and p38MAPK [PMID:10866661, PMID:11971985, PMID:16456540, PMID:18765637, PMID:19339517]; cell-cycle phosphorylation by CDK1/Cyclin B that excludes it from mitotic chromatin [PMID:22163316]; counteracting dephosphorylation and stabilization by PP1/PP2A/PDXP [PMID:18922467]; sumoylation by PIAS1 and arginine methylation by CARM1 that restrain activity [PMID:17043108, PMID:22283414]; and proteasomal degradation through the REGγ/20S proteasome and the PTEN–Fbw7α ubiquitin pathway [PMID:16439211, PMID:23514585]. Its subcellular distribution is set by microtubule-dependent nuclear–cytoplasmic shuttling, with histone acetyltransferase activity confined to nuclear complexes [PMID:12192059]. In vivo, NCOA3 is required for normal growth, female reproduction, and mammary development [PMID:10823921], for embryonic stem cell pluripotency via Esrrb and Nanog [PMID:23019124, PMID:22977234], and for regulatory T cell induction [PMID:33564037], while its oncogenic overexpression drives breast and prostate cancer through an autocrine IGF-I/PI3K/AKT loop, MMP-mediated invasion, and EMT [PMID:15380517, PMID:14996752, PMID:18644862, PMID:23762395].","teleology":[{"year":1997,"claim":"Established NCOA3 as a ligand-dependent nuclear receptor coactivator with intrinsic enzymatic activity, defining its core molecular function.","evidence":"Co-IP, reporter assays, in vitro HAT assays, and far-Western cloning across ER, TR, and other nuclear receptors","pmids":["9252329","9267036","9192892","9346901"],"confidence":"High","gaps":["In vivo target gene repertoire not yet mapped","Distinct binding surfaces among coactivators only partially resolved"]},{"year":2000,"claim":"Linked growth-factor signaling to coactivator output and demonstrated physiological in vivo requirement, showing NCOA3 integrates kinase signaling with hormone action.","evidence":"In vitro/in vivo MAPK kinase assays, endogenous co-IP in MCF-7 cells, and a SRC-3 knockout mouse with growth and reproductive phenotypes; AR coactivation by yeast two-hybrid and reporter assays","pmids":["10866661","11050174","10823921","10965917"],"confidence":"High","gaps":["Specific MAPK phosphosites mapped only later","Tissue-specific contributions to knockout phenotype unresolved"]},{"year":2002,"claim":"Defined NCOA3 regulation of NF-κB signaling and the spatial control of its activity, showing compartment dictates enzymatic function.","evidence":"Biochemical purification with MS, IKK kinase assay, TNFα-induced translocation; immunofluorescence, GFP imaging, leptomycin B, and HAT assays mapping CRM1-dependent shuttling","pmids":["11971985","12192059"],"confidence":"High","gaps":["Trigger linking cell-cycle phase to shuttling not defined","How cytoplasmic pool is reactivated unresolved"]},{"year":2004,"claim":"Identified the oncogenic mechanism of NCOA3 overexpression in cancer and a receptor-independent proliferative route via E2F1.","evidence":"Transgenic and knockout mouse tumor models, RNAi, ChIP at E2F and IGF-I loci, PI3K/AKT pathway analysis, and ERα degradation assays","pmids":["15169882","15289619","15380517","14996752"],"confidence":"High","gaps":["Relative contribution of receptor-dependent vs E2F1 routes in tumors unquantified","Direct vs indirect IGF-I transcriptional control not fully resolved"]},{"year":2006,"claim":"Resolved how NCOA3 abundance and activity are turned down through proteolysis and modification, establishing a layered degradation/PTM control system.","evidence":"In vitro reconstitution with purified REGγ/20S proteasome, in vivo sumoylation/phosphorylation assays, p38MAPK kinase assays in RARα context, and CARM1 in vitro methylation with KO MEF validation","pmids":["16439211","16760465","16456540","17043108"],"confidence":"High","gaps":["Interplay/ordering of competing modifications not integrated","Cellular cues selecting degradation route unclear"]},{"year":2008,"claim":"Expanded the kinase and phosphatase regulatory map and structurally explained coactivator folding and AR selectivity, plus invasion/metastasis functions.","evidence":"c-Abl kinase assays with phospho-mutants, phosphatase functional genomic screen with in vitro dephosphorylation, NMR of the ACTR–CBP complex, ChIP at MMP promoters, and knockout PyMT metastasis models","pmids":["18765637","18593949","18644862","18177052","18922467"],"confidence":"High","gaps":["Combinatorial logic of multiple phosphosites unresolved","Phosphatase substrate specificity in vivo incompletely defined"]},{"year":2010,"claim":"Provided structural basis for AR-coactivator preference and extended coactivation to ERRα and neuronal miRNA pathways.","evidence":"Crystal structure of SRC3-AR with patient mutation analysis, ATBF1 competition assays, FRET/two-hybrid/endogenous co-IP for ERRα, and Ncoa3 knockdown affecting Ago2 and dendritic morphology","pmids":["20086010","20720010","19491275","26105073"],"confidence":"High","gaps":["Generality of LXXLL synergy across receptors untested","Mechanism of Ago2 transcriptional control not defined"]},{"year":2012,"claim":"Established NCOA3 roles in stem cell pluripotency, mitotic chromatin exclusion, and metabolic regulation, broadening its physiological scope.","evidence":"Co-IP and ChIP-seq with Esrrb in ESCs, ChIP at Nanog promoter, CDK1/Cyclin B kinase assays with mitotic fractionation, PIAS1 E3-mutant sumoylation assays, and double-knockout metabolic mouse models","pmids":["23019124","22977234","22163316","22283414","22859932"],"confidence":"High","gaps":["Direct vs indirect pluripotency targets partially resolved","Functional consequence of mitotic redistribution on later transcription unclear"]},{"year":2014,"claim":"Connected NCOA3 to ubiquitin-bridge degradation, chromatin remodeling at mucin loci, EMT, and UPR signaling, linking it to cancer cell plasticity and stress responses.","evidence":"PTEN-Fbw7α bridging co-IP/ubiquitination assays, SNAI1 promoter and E-cadherin analyses, MUC4 nuclease accessibility/FUT8 assays, and XBP1-PERK-ATF4 UPR feedback experiments","pmids":["23514585","23762395","25531332","27109102"],"confidence":"Medium","gaps":["Most mechanisms from single labs without reciprocal validation","Direct vs cofactor-mediated chromatin remodeling at MUC4 not separated"]},{"year":2018,"claim":"Identified additional degradation regulators and a cancer stem cell function, supporting NCOA3 as a therapeutic target.","evidence":"MAD2L2/p38-dependent ubiquitination assays and tumor models; PELP1-AIB1 complex with Thr24 phospho-readout, SI-2 inhibition, and tumorsphere assays","pmids":["29360267","29348189"],"confidence":"Medium","gaps":["Single-lab mechanisms awaiting independent confirmation","Direct kinase responsible for Thr24 phosphorylation not defined"]},{"year":2021,"claim":"Extended NCOA3 function to immune regulation, showing a requirement for regulatory T cell induction and suppressive activity.","evidence":"Bioinformatic enrichment plus cellular loss-of-function and pharmacological inhibition with T cell suppression assays","pmids":["33564037"],"confidence":"Medium","gaps":["Transcriptional targets in Tregs not identified","Mechanism of SRC-3 enrichment in Tregs unknown"]},{"year":null,"claim":"How the dozens of competing post-translational modifications, degradation routes, and partner interactions are dynamically integrated to set NCOA3 activity in a given cellular and disease context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of PTM crosstalk","Context-specific target gene programs not systematically mapped","Structural basis of full-length complex assembly unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,11,29]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,24]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,7,25,41]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,12,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,9,38]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[11,22,29]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,13,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16,19,24,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,22,34]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,10,35]}],"complexes":["CBP/p300 coactivator complex","IKK complex"],"partners":["ESR1","AR","EP300","CARM1","E2F1","ESRRB","ESRRA","PELP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6Q9","full_name":"Nuclear receptor coactivator 3","aliases":["ACTR","Amplified in breast cancer 1 protein","AIB-1","CBP-interacting protein","pCIP","Class E basic helix-loop-helix protein 42","bHLHe42","Receptor-associated coactivator 3","RAC-3","Steroid receptor coactivator protein 3","SRC-3","Thyroid hormone receptor activator molecule 1","TRAM-1"],"length_aa":1424,"mass_kda":155.3,"function":"Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Plays a central role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ER), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Displays histone acetyltransferase activity. Also involved in the coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y6Q9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NCOA3","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":true,"resolved_as":"RAC3","ensg_id":"ENSG00000169750","cell_line_id":"CID000608","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"membrane","grade":2},{"compartment":"golgi","grade":1},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000608","total_profiled":1310},"omim":[{"mim_id":"614777","title":"MMS19 HOMOLOG, CYTOSOLIC IRON-SULFUR ASSEMBLY COMPONENT; MMS19","url":"https://www.omim.org/entry/614777"},{"mim_id":"614610","title":"KN MOTIF- AND ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 2; KANK2","url":"https://www.omim.org/entry/614610"},{"mim_id":"611941","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 2; ATAD2","url":"https://www.omim.org/entry/611941"},{"mim_id":"611192","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 11; ANKRD11","url":"https://www.omim.org/entry/611192"},{"mim_id":"606127","title":"MYOCARDIN; MYOCD","url":"https://www.omim.org/entry/606127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCOA3"},"hgnc":{"alias_symbol":["RAC3","AIB1","ACTR","p/CIP","TRAM-1","CAGH16","TNRC16","KAT13B","bHLHe42","SRC-3","SRC3"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6Q9","domains":[{"cath_id":"-","chopping":"43-84","consensus_level":"medium","plddt":77.4819,"start":43,"end":84},{"cath_id":"3.30.450.20","chopping":"123-175_192-205_219-259","consensus_level":"medium","plddt":81.4924,"start":123,"end":259},{"cath_id":"3.30.450.20","chopping":"267-376","consensus_level":"high","plddt":84.8795,"start":267,"end":376}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Q9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Q9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Q9-F1-predicted_aligned_error_v6.png","plddt_mean":48.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCOA3","jax_strain_url":"https://www.jax.org/strain/search?query=NCOA3"},"sequence":{"accession":"Q9Y6Q9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6Q9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6Q9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Q9"}},"corpus_meta":[{"pmid":"9252329","id":"PMC_9252329","title":"AIB1, 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\"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"AIB1 (NCOA3) protein interacts with estrogen receptors in a ligand-dependent fashion and enhances estrogen-dependent transcription when transfected into cells.\",\n      \"method\": \"Co-immunoprecipitation, transfection/reporter assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand-dependent interaction demonstrated by co-IP and functional transactivation assay, independently replicated across multiple labs in subsequent studies\",\n      \"pmids\": [\"9252329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ACTR (NCOA3) is a histone acetyltransferase that directly binds nuclear receptors in a hormone-dependent manner and recruits CBP and P/CAF to form a multisubunit coactivator complex containing at least three classes of histone acetyltransferases.\",\n      \"method\": \"In vitro HAT assay with purified ACTR, co-immunoprecipitation, direct binding assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified protein, plus reciprocal co-IP for complex formation; foundational biochemical study\",\n      \"pmids\": [\"9267036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"p/CIP (NCOA3) is present in cells as a complex with CBP and is required for transcriptional activity of nuclear receptors and CBP/p300-dependent transcription factors; leucine-rich charged helical interaction motifs in p/CIP are required for receptor-specific gene activation.\",\n      \"method\": \"Co-immunoprecipitation, transfection/reporter assay, deletion mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical complex identification by co-IP, functional validation by mutagenesis and reporter assay, replicated by independent labs\",\n      \"pmids\": [\"9192892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TRAM-1 (NCOA3) binds thyroid hormone receptor and other nuclear receptors in a ligand-dependent manner via a region outside the AF-2 domain (including helix 3 of the ligand binding domain), distinct from SRC-1 binding.\",\n      \"method\": \"Far-Western expression screening, GST pulldown, transfection/reporter assay, AF-2 and helix-3 mutant TR binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — far-Western cloning, direct binding assays with LBD mutants, and functional transactivation assays in a single rigorous study\",\n      \"pmids\": [\"9346901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AIB1 (NCOA3) is a phosphoprotein that is phosphorylated in vitro and in vivo by MAPK; MAPK phosphorylation of AIB1 enhances its transcriptional activity and stimulates recruitment of p300 and associated histone acetyltransferase activity, providing a mechanism for growth factor modulation of estrogen action.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation analysis, co-immunoprecipitation, reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with purified MAPK plus in vivo phosphorylation and functional co-IP in same study\",\n      \"pmids\": [\"10866661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Endogenous AIB1 and estrogen receptor form a ligand-specific complex in MCF-7 breast cancer cells detectable by immunoprecipitation; complex formation is observed with estradiol but much less with the partial agonist monohydroxytamoxifen. In vitro binding affinity of mouse ER for AIB1 is ~40–120 nM.\",\n      \"method\": \"Immunoprecipitation of endogenous proteins, in vitro binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP in intact cells plus quantitative in vitro binding, demonstrating physiological relevance\",\n      \"pmids\": [\"11050174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SRC-3/NCOA3 knockout mice exhibit dwarfism, delayed puberty, reduced female reproductive function, and blunted mammary gland development, demonstrating in vivo roles in the growth hormone regulatory pathway and estrogen production.\",\n      \"method\": \"Genetic knockout mouse model with hormonal and phenotypic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with pleiotropic phenotypic readouts and hormonal analysis, replicated/confirmed across multiple studies\",\n      \"pmids\": [\"10823921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TRAM-1 (NCOA3) acts as an androgen receptor (AR) coactivator: it binds the AR ligand-binding domain and the N-terminal/DNA-binding domains in a ligand-dependent manner and enhances DHT-dependent AR transactivation ~5-fold in cell-based assays.\",\n      \"method\": \"Yeast two-hybrid, GST affinity matrix binding assay, transfection/reporter assay, immunohistochemistry\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro GST pulldown and functional transactivation in mammalian cells, single lab\",\n      \"pmids\": [\"10965917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SRC-3 (NCOA3) associates with the IκB kinase (IKK) complex (but not SRC-1), is phosphorylated by IKK in vitro, and undergoes TNFα-induced phosphorylation and translocation from cytoplasm to nucleus in cells; SRC-3 enhances NF-κB-mediated gene expression in concert with IKK.\",\n      \"method\": \"Biochemical purification of SRC-3 protein complexes, mass spectrometry identification, in vitro kinase assay, subcellular fractionation/immunofluorescence, reporter assay, SRC-3 null mouse gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical purification with MS identification, in vitro kinase assay, cellular localization experiment, and genetic evidence from knockout mice\",\n      \"pmids\": [\"11971985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p/CIP (NCOA3) is predominantly cytoplasmic in many cell types; nuclear import and export are regulated by an N-terminal nuclear import signal and C-terminal leucine-rich CRM1-dependent nuclear export sequences; cytoplasmic shuttling is cell cycle-dependent (S and late M phases) and requires an intact microtubule network; only nuclear p/CIP complexes possess histone acetyltransferase activity.\",\n      \"method\": \"Immunofluorescence, live cell imaging with GFP fusions, leptomycin B treatment, immunoaffinity purification with HAT assay, deletion/point mutagenesis, fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal localization methods, functional consequence (HAT activity linked to compartment), mutagenesis confirming export sequences\",\n      \"pmids\": [\"12192059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p/CIP (NCOA3) recruits GCN5 histone acetyltransferase via its AD1 activation domain to facilitate RARα-dependent transcription; two helical motifs within AD1 are required for interactions with both GCN5 and CBP.\",\n      \"method\": \"Yeast genetic screen (SAGA component mutants), co-immunoprecipitation, siRNA knockdown, reporter assay, deletion and point mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast epistasis combined with mammalian co-IP, siRNA, reporter assays, and mutagenesis in one study\",\n      \"pmids\": [\"12885766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ACTR/NCOA3 directly interacts with E2F1 through its N-terminal domain and is recruited to E2F target gene promoters, stimulating transcription of G1/S transition genes independently of estrogen receptor, thereby promoting breast cancer cell proliferation and antiestrogen resistance.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, adenoviral RNAi, reporter assay, cell proliferation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ChIP, functional RNAi knockdown with specific proliferation phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15169882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AIB1 coactivator uniquely mediates agonist-induced (but not antagonist-induced) ERα degradation via the ubiquitin-proteasome machinery; AIB1 recruitment by ERα is both necessary and sufficient to promote ERα degradation and is required for RNA polymerase II recruitment to ERα target promoters.\",\n      \"method\": \"RNAi knockdown, chromatin immunoprecipitation, reporter assay, Western blot for ERα stability\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts (ER stability, PolII recruitment, target gene transcription) in one study\",\n      \"pmids\": [\"15289619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AIB1 overexpression in transgenic mice leads to increased mammary IGF-I mRNA and serum IGF-I protein, with activation of IGF-I receptor and downstream PI3K/AKT signaling in mammary epithelial cells; AIB1 knockdown in tumor cells reduces IGF-I mRNA and increases apoptosis, demonstrating an autocrine IGF-I loop as the oncogenic mechanism.\",\n      \"method\": \"Transgenic mouse model, siRNA knockdown, signaling pathway analysis (Western blot for IGF-IR, PI3K/AKT), apoptosis assay\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic gain-of-function plus RNAi loss-of-function with defined molecular pathway, replicated across mouse and cell models\",\n      \"pmids\": [\"15380517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AIB1 deficiency in AIB1(-/-)/v-Ha-ras mice causes partial resistance to IGF-I signaling due to significant reduction in insulin receptor substrates, suppressing mammary tumorigenesis and metastasis by inhibiting cell proliferation and migration.\",\n      \"method\": \"Genetic knockout in mammary tumor model, IGF-I signaling pathway analysis, tumor incidence assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout genetic model with defined molecular pathway (IRS reduction) and functional phenotype (tumor suppression)\",\n      \"pmids\": [\"14996752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"p/CIP (NCOA3) acts as a positive regulator of STAT6 transcriptional activation by indirectly interacting with STAT6 via p300/CBP; overexpression of the CBP-interacting domain of p/CIP blocks STAT6-mediated transactivation and CD23 expression in IL-4-stimulated B cells. ChIP demonstrates IL-4-induced recruitment of p/CIP to the IgH germ-line ε promoter.\",\n      \"method\": \"Co-immunoprecipitation, reporter assay, chromatin immunoprecipitation, overexpression/dominant-negative approach\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and reporter assay in single lab; STAT6 interaction is indirect (via p300)\",\n      \"pmids\": [\"15145939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRC-3/AIB1 (NCOA3) is degraded by the REGγ proteasome in a ubiquitin- and ATP-independent manner; REGγ directly interacts with SRC-3 and promotes its degradation by the 20S proteasome, as demonstrated by in vitro reconstitution with purified REGγ, SRC-3, and 20S proteasome.\",\n      \"method\": \"In vitro proteasome proteolysis assay with purified components, RNAi knockdown and overexpression, reporter assay for ER target gene expression\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins plus cellular gain/loss-of-function experiments with functional readouts\",\n      \"pmids\": [\"16439211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AIB1 (NCOA3) is sumoylated, and sumoylation attenuates its transactivation activity; estrogen treatment leads to increased phosphorylation and decreased sumoylation of AIB1; sumoylation and phosphorylation coordinately regulate AIB1 transcriptional output.\",\n      \"method\": \"In vivo sumoylation assay, phosphorylation analysis, reporter assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo sumoylation and phosphorylation analyses with reporter assay, single lab, two methods\",\n      \"pmids\": [\"16760465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRC-3/NCOA3 is phosphorylated by p38MAPK during retinoic acid (RA)-dependent RARα activation; this phosphorylation first facilitates RARα target gene activation by controlling the dynamics of SRC-3/RARα interactions, then promotes SRC-3 degradation to inhibit transcription; phosphorylation and degradation occur specifically within the context of RARα complexes.\",\n      \"method\": \"In vitro kinase assay, p38MAPK inhibitor treatment, Western blot, reporter assay, protein stability assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus specific inhibitor and functional reporter assay, single lab\",\n      \"pmids\": [\"16456540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARM1 methylates p/CIP (NCOA3) at three conserved arginine residues in a glutamine-rich C-terminal region; CARM1 is the required methyltransferase (not other PRMTs); methylation increases p/CIP turnover by enhanced degradation and impairs p/CIP association with CBP, thereby negatively impacting transcription.\",\n      \"method\": \"In vitro methylation assay, metabolic labeling, mass spectrometry identification of methylation sites, CARM1 knockout MEF extracts, CBP co-immunoprecipitation, methylation site mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, MS site identification, genetic knockout validation, and functional co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"17043108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRC-3/AIB1 is phosphorylated at C-terminal tyrosine Y1357 by c-Abl kinase; this phosphorylation is induced by IGF-I, EGF, and estrogen and is required for AIB1 coactivation of ERα, PR-B, NF-κB, and AP-1 promoters; Y1357 phosphorylation modulates AIB1 association with c-Abl, ERα, p300, and CARM1.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, co-immunoprecipitation, reporter assay, imatinib inhibitor treatment, cell growth and focus formation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with specific kinase plus phospho-site mutagenesis, co-IP, and functional reporter/phenotypic assays in one study\",\n      \"pmids\": [\"18765637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRC-3/AIB1 is required for focal adhesion turnover, focal adhesion kinase activation, and directly regulates transcription of MMP-2 and MMP-13 through coactivation of AP-1 and PEA3, promoting prostate cancer cell migration and invasion.\",\n      \"method\": \"siRNA knockdown, focal adhesion turnover assay, chromatin immunoprecipitation, reporter assay, invasion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined molecular pathway (focal adhesion kinase, ChIP for MMP promoters), single lab\",\n      \"pmids\": [\"18593949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AIB1 serves as a PEA3 coactivator and forms complexes with PEA3 on MMP2 and MMP9 promoters to enhance their expression in breast cancer cells; AIB1 deficiency reduces lung metastasis in the PyMT mouse model and AIB1-null tumor cells maintain epithelial markers and form polarized acinar structures unlike wild-type tumor cells.\",\n      \"method\": \"Knockout mouse/tumor transplantation model, chromatin immunoprecipitation, reporter assay, 3D culture, invasion assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model plus ChIP at defined promoters plus cell biology assays, multiple orthogonal methods\",\n      \"pmids\": [\"18644862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ACTR/AIB1 (NCOA3) binds NCBD domain of CBP/p300 through mutual synergistic folding; the free ACTR activation domain (residues 1041-1088) is completely unfolded in isolation but forms a well-ordered helical complex upon binding to CBP; backbone dynamics of the complex are consistent with a fully folded protein.\",\n      \"method\": \"NMR relaxation (15N longitudinal/transverse rates, heteronuclear NOE), secondary chemical shift analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous NMR structural and dynamic characterization; defines mechanism of coupled folding-binding\",\n      \"pmids\": [\"18177052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PP1, PP2A, and PDXP are key negative regulators of SRC-3/AIB1 coactivator activity; PDXP and PP2A dephosphorylate SRC-3 and inhibit its ligand-dependent association with estrogen receptor; PP1 stabilizes SRC-3 by dephosphorylating a phospho-degron at Ser101/Ser102, preventing proteasome-dependent turnover; PP1 regulates SRC-3-dependent cell proliferation and invasion in breast cancer cells.\",\n      \"method\": \"Functional genomic phosphatase screen, in vitro dephosphorylation assay, co-immunoprecipitation, SRC-3 stability assay, cell proliferation and invasion assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-scale functional screen followed by biochemical validation (in vitro dephosphorylation), site identification, and cellular phenotypic assays\",\n      \"pmids\": [\"18922467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRC3/AIB1 (NCOA3) interacts with hormone-activated androgen receptor via synergistic binding of its first and third LXXLL motifs; crystal structure reveals the molecular basis for AR's preference for SRC3 over other coactivators; AR mutations found in prostate cancer patients correlate with their SRC3 binding potency.\",\n      \"method\": \"Crystal structure determination, mutagenesis, biochemical binding assays, functional transactivation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis and biochemical/functional validation in one rigorous study\",\n      \"pmids\": [\"20086010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATBF1 inhibits estrogen receptor function by selectively competing with AIB1 but not GRIP1 or SRC-1 for binding to ERα; ATBF1 physically interacts with ER via multiple domains in both proteins and inhibits ER-mediated gene transcription and cell growth.\",\n      \"method\": \"In vitro and in vivo co-immunoprecipitation, competitive binding assay, reporter assay, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo co-IP with functional reporter and cell growth assays, single lab\",\n      \"pmids\": [\"20720010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NCOA3 (SRC-3) promotes Ago2 expression at the transcriptional level in hippocampal neurons, thereby stimulating miRNA function; Ncoa3 knockdown reduces dendritic complexity and dendritic spine maturation in a miRNA-dependent manner that can be rescued by Ago2 overexpression.\",\n      \"method\": \"RNAi knockdown, Ago2 overexpression rescue, fluorescence microscopy for dendritic morphology, reporter assays for miRNA function\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with specific rescue, two orthogonal readouts (Ago2 expression, dendritic morphology), single lab\",\n      \"pmids\": [\"26105073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AIB1 (NCOA3) is phosphorylated at Ser728 and Ser867 by CDK1/Cyclin B at the onset of mitosis; this phosphorylation correlates with exclusion of AIB1 from condensed chromatin and redistribution to the cell periphery without affecting its transcriptional properties; PP1 likely mediates dephosphorylation at mitotic exit.\",\n      \"method\": \"In vitro kinase assay, specific kinase inhibitors, phospho-specific antibody, Western blot, fluorescence microscopy, subcellular fractionation, luciferase reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus phospho-site mutagenesis, subcellular fractionation with fluorescence microscopy, and functional reporter assay in one study\",\n      \"pmids\": [\"22163316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ncoa3 interacts with the orphan nuclear receptor Esrrb via its ligand-binding domain and bridges Esrrb to RNA polymerase II complexes; Ncoa3 is required for induction and maintenance of pluripotency in embryonic stem cells and shares genome-wide gene regulatory functions with Esrrb at active enhancers through cooperation with the Oct4-Sox2-Nanog circuitry.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-sequencing, microarray gene expression analysis, RNAi knockdown, ESC self-renewal and differentiation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP-seq genome-wide mapping, microarray, and functional knockdown with pluripotency readouts, multiple orthogonal methods\",\n      \"pmids\": [\"23019124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ncoa3 binds the Nanog promoter and recruits CBP (histone acetyltransferase) and CARM1 (histone arginine methyltransferase) to activate Nanog expression in mouse ESCs; GSK3 signaling downregulates Ncoa3 protein level to suppress Nanog expression.\",\n      \"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation, RNAi knockdown, reporter assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP with functional knockdown readouts, single lab\",\n      \"pmids\": [\"22977234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PIAS1 is the SUMO E3 ligase responsible for AIB1 sumoylation; PIAS1 co-immunoprecipitates with AIB1, and overexpression of wild-type PIAS1 (but not the E3 ligase-dead C350S mutant) increases AIB1 sumoylation, promotes AIB1 stability, represses AIB1 transcriptional activity, and attenuates AIB1 interaction with ERα, reducing cell growth.\",\n      \"method\": \"Co-immunoprecipitation, sumoylation assay, reporter assay, PIAS1 E3 ligase mutant, cell proliferation assay\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with E3 ligase mutant validation and functional reporter assay, single lab\",\n      \"pmids\": [\"22283414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p/CIP (NCOA3) and SRC-1 cooperatively regulate insulin signaling through IRS1: deletion of both coactivators significantly increases IRS1 expression in fat and muscle cells and in vivo, enhancing insulin sensitivity and glucose metabolism.\",\n      \"method\": \"Double knockout mouse model, gene expression analysis, glucose uptake assay, insulin sensitivity testing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-knockout model with specific IRS1 molecular readout and metabolic phenotype, single lab\",\n      \"pmids\": [\"22859932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTEN interacts with AIB1 via its phosphatase domain and acts as a bridge between AIB1 and the E3 ubiquitin ligase Fbw7α (via PTEN's C2 domain), promoting ubiquitin-mediated degradation of AIB1 in a phosphatase-activity-independent manner, thereby reducing AIB1 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, PTEN phosphatase mutant, cell proliferation assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying bridge mechanism, phosphatase-dead mutant, functional knockdown, single lab\",\n      \"pmids\": [\"23514585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AIB1 cooperates with ERα to promote EMT in breast cancer cells through activation of SNAI1 transcription; AIB1-ERα complex binds ERα-binding sites on the SNAI1 promoter to upregulate SNAI1, which represses E-cadherin expression; this requires an ERα-binding site on SNAI1 promoter.\",\n      \"method\": \"Overexpression and knockdown of AIB1 and SNAI1, E-cadherin expression analysis, migration/invasion assay, promoter analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation with defined promoter dependence and multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"23762395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NCOA3 regulates MUC4 promoter accessibility (chromatin remodeling) as demonstrated by micrococcal nuclease digestion and ChIP assays; NCOA3 knockdown abrogates retinoic acid-mediated MUC4 upregulation; NCOA3 also stabilizes mucins (MUC4 and MUC1) post-translationally through fucosylation via FUT8.\",\n      \"method\": \"Chromatin immunoprecipitation, micrococcal nuclease digestion assay, siRNA knockdown, gene expression analysis, FUT8 knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and nuclease accessibility assay plus FUT8 knockdown validation, single lab\",\n      \"pmids\": [\"25531332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NCOA3 is a transcriptional target of XBP1; NCOA3 is required for optimal activation of the PERK-eIF2α-ATF4 pathway during UPR; NCOA3 is required for XBP1 induction during estrogen stimulation, forming a positive feedback loop maintaining high NCOA3 and XBP1 levels in breast cancer cells.\",\n      \"method\": \"RNAi knockdown, reporter assay, Western blot for UPR pathway components, promoter analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined pathway readouts (PERK-ATF4 activation), reporter assay for XBP1-NCOA3 feedback, single lab\",\n      \"pmids\": [\"27109102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MAD2L2 (REV7) interacts with NCOA3, and MAD2L2 overexpression suppresses NCOA3 by activating p38 kinase, which phosphorylates NCOA3 and leads to its ubiquitination and proteasomal degradation.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, co-immunoprecipitation, p38 inhibitor, Western blot for NCOA3 stability, ubiquitination assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus biochemical validation of mechanism (p38-dependent phosphorylation leading to ubiquitination), single lab\",\n      \"pmids\": [\"29360267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cytoplasmic PELP1 forms a complex with AIB1 (NCOA3), elevates AIB1 phosphorylation at Thr24, and promotes cancer stem cell-like (ALDH+) tumorsphere formation; direct manipulation of AIB1 levels or pharmacological inhibition of AIB1 abrogates cytoplasmic PELP1-induced tumorsphere formation.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific Western blot, shRNA knockdown, tumorsphere/ALDH assay, AIB1 inhibitor (SI-2), syngeneic in vivo tumor model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus shRNA and pharmacological inhibition with specific phenotypic readout, single lab\",\n      \"pmids\": [\"29348189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CK1δ phosphorylates AIB1 at a novel site (S601) and ERα in vitro; CK1δ interacts with ERα and AIB1 in vivo and increases ERα-AIB1 association; CK1δ overexpression promotes AIB1 protein stability in an estradiol-dependent manner; CK1δ silencing reduces ERα transcriptional activity and decreases AIB1 levels via proteasome-mediated degradation.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, proteasome inhibitor treatment, Western blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus cellular co-IP and functional reporter assay, single lab\",\n      \"pmids\": [\"19339517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRC-3 (NCOA3) is enriched in regulatory T cells (Tregs) in mice and humans; SRC-3 depletion or pharmacological inhibition causes failure of Treg induction from resting T cells and loss of ability to suppress proliferation of stimulated T cells.\",\n      \"method\": \"Bioinformatics analysis of public data, directed cellular assays, pharmacological inhibition, T cell suppression assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bioinformatics plus cellular loss-of-function with specific Treg functional readouts, single lab\",\n      \"pmids\": [\"33564037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AIB1 directly interacts with ERRα as demonstrated by FRET, mammalian two-hybrid, and co-immunoprecipitation of endogenous proteins; AIB1 enhances ERRα transcriptional activity in ERα-negative breast cancer cell lines; both proteins are recruited to ERRα target gene promoters; blocking ERRα with an inverse agonist abolishes AIB1-ERRα interaction and coactivation.\",\n      \"method\": \"FRET, mammalian two-hybrid, endogenous co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, inverse agonist treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent interaction assays (FRET, two-hybrid, endogenous co-IP) plus ChIP and functional reporter, single lab but highly rigorous\",\n      \"pmids\": [\"19491275\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA3 (AIB1/SRC-3/ACTR) is a multifunctional transcriptional coactivator that binds ligand-activated nuclear receptors (ER, AR, TR, RARα, ERRα, Esrrb, and others) and non-receptor transcription factors (E2F1, NF-κB, AP-1, PEA3, STAT6) to recruit histone-modifying enzymes (CBP/p300, P/CAF, GCN5, CARM1) and chromatin-remodeling machinery; its activity and stability are tightly regulated by multiple post-translational modifications including phosphorylation by MAPK, IKK, p38MAPK, CDK1/CyclinB, CK1δ, c-Abl, and dephosphorylation by PP1/PP2A/PDXP, sumoylation by PIAS1, arginine methylation by CARM1, and ubiquitin-mediated degradation via the REGγ/20S proteasome or Fbw7α E3 ligase; subcellular localization is regulated by microtubule-dependent nuclear-cytoplasmic shuttling and cell-cycle-dependent chromatin exclusion (via CDK1 phosphorylation at mitosis); in vivo, NCOA3 is required for normal growth, female reproduction, mammary gland development, placentation, ESC pluripotency, and Treg function, and its oncogenic overexpression drives breast and other cancers through IGF-I/PI3K/AKT autocrine signaling, MMP-mediated invasion, E2F1-dependent cell cycle progression, and UPR pathway activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCOA3 (AIB1/SRC-3/ACTR/p/CIP/TRAM-1) is a multifunctional transcriptional coactivator that couples ligand-activated nuclear receptors to chromatin-modifying machinery to drive hormone-dependent gene expression, growth, and oncogenesis [#0, #1]. It binds nuclear receptors including estrogen receptor, thyroid hormone receptor, androgen receptor, and ERRα in a ligand-dependent manner through LXXLL/helical interaction motifs, with crystallographic and binding data defining receptor selectivity [#0, #3, #7, #25, #41]. Bound to receptors and to non-receptor factors such as E2F1, NF-κB, AP-1, PEA3, and STAT6, NCOA3 functions as an intrinsic histone acetyltransferase and as an assembly platform that recruits CBP/p300, P/CAF, and GCN5 acetyltransferases and the arginine methyltransferase CARM1 to target promoters [#1, #10, #11, #15, #21]; its activation domain is intrinsically disordered and folds upon binding the NCBD of CBP/p300 [#23]. NCOA3 activity and abundance are governed by an extensive post-translational network: activating phosphorylation by MAPK, IKK, c-Abl, CK1δ, and p38MAPK [#4, #8, #18, #20, #39]; cell-cycle phosphorylation by CDK1/Cyclin B that excludes it from mitotic chromatin [#28]; counteracting dephosphorylation and stabilization by PP1/PP2A/PDXP [#24]; sumoylation by PIAS1 and arginine methylation by CARM1 that restrain activity [#19, #31]; and proteasomal degradation through the REGγ/20S proteasome and the PTEN–Fbw7α ubiquitin pathway [#16, #33]. Its subcellular distribution is set by microtubule-dependent nuclear–cytoplasmic shuttling, with histone acetyltransferase activity confined to nuclear complexes [#9]. In vivo, NCOA3 is required for normal growth, female reproduction, and mammary development [#6], for embryonic stem cell pluripotency via Esrrb and Nanog [#29, #30], and for regulatory T cell induction [#40], while its oncogenic overexpression drives breast and prostate cancer through an autocrine IGF-I/PI3K/AKT loop, MMP-mediated invasion, and EMT [#13, #14, #22, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established NCOA3 as a ligand-dependent nuclear receptor coactivator with intrinsic enzymatic activity, defining its core molecular function.\",\n      \"evidence\": \"Co-IP, reporter assays, in vitro HAT assays, and far-Western cloning across ER, TR, and other nuclear receptors\",\n      \"pmids\": [\"9252329\", \"9267036\", \"9192892\", \"9346901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo target gene repertoire not yet mapped\", \"Distinct binding surfaces among coactivators only partially resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked growth-factor signaling to coactivator output and demonstrated physiological in vivo requirement, showing NCOA3 integrates kinase signaling with hormone action.\",\n      \"evidence\": \"In vitro/in vivo MAPK kinase assays, endogenous co-IP in MCF-7 cells, and a SRC-3 knockout mouse with growth and reproductive phenotypes; AR coactivation by yeast two-hybrid and reporter assays\",\n      \"pmids\": [\"10866661\", \"11050174\", \"10823921\", \"10965917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific MAPK phosphosites mapped only later\", \"Tissue-specific contributions to knockout phenotype unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined NCOA3 regulation of NF-κB signaling and the spatial control of its activity, showing compartment dictates enzymatic function.\",\n      \"evidence\": \"Biochemical purification with MS, IKK kinase assay, TNFα-induced translocation; immunofluorescence, GFP imaging, leptomycin B, and HAT assays mapping CRM1-dependent shuttling\",\n      \"pmids\": [\"11971985\", \"12192059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger linking cell-cycle phase to shuttling not defined\", \"How cytoplasmic pool is reactivated unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the oncogenic mechanism of NCOA3 overexpression in cancer and a receptor-independent proliferative route via E2F1.\",\n      \"evidence\": \"Transgenic and knockout mouse tumor models, RNAi, ChIP at E2F and IGF-I loci, PI3K/AKT pathway analysis, and ERα degradation assays\",\n      \"pmids\": [\"15169882\", \"15289619\", \"15380517\", \"14996752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of receptor-dependent vs E2F1 routes in tumors unquantified\", \"Direct vs indirect IGF-I transcriptional control not fully resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how NCOA3 abundance and activity are turned down through proteolysis and modification, establishing a layered degradation/PTM control system.\",\n      \"evidence\": \"In vitro reconstitution with purified REGγ/20S proteasome, in vivo sumoylation/phosphorylation assays, p38MAPK kinase assays in RARα context, and CARM1 in vitro methylation with KO MEF validation\",\n      \"pmids\": [\"16439211\", \"16760465\", \"16456540\", \"17043108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay/ordering of competing modifications not integrated\", \"Cellular cues selecting degradation route unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Expanded the kinase and phosphatase regulatory map and structurally explained coactivator folding and AR selectivity, plus invasion/metastasis functions.\",\n      \"evidence\": \"c-Abl kinase assays with phospho-mutants, phosphatase functional genomic screen with in vitro dephosphorylation, NMR of the ACTR–CBP complex, ChIP at MMP promoters, and knockout PyMT metastasis models\",\n      \"pmids\": [\"18765637\", \"18593949\", \"18644862\", \"18177052\", \"18922467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic of multiple phosphosites unresolved\", \"Phosphatase substrate specificity in vivo incompletely defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided structural basis for AR-coactivator preference and extended coactivation to ERRα and neuronal miRNA pathways.\",\n      \"evidence\": \"Crystal structure of SRC3-AR with patient mutation analysis, ATBF1 competition assays, FRET/two-hybrid/endogenous co-IP for ERRα, and Ncoa3 knockdown affecting Ago2 and dendritic morphology\",\n      \"pmids\": [\"20086010\", \"20720010\", \"19491275\", \"26105073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of LXXLL synergy across receptors untested\", \"Mechanism of Ago2 transcriptional control not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established NCOA3 roles in stem cell pluripotency, mitotic chromatin exclusion, and metabolic regulation, broadening its physiological scope.\",\n      \"evidence\": \"Co-IP and ChIP-seq with Esrrb in ESCs, ChIP at Nanog promoter, CDK1/Cyclin B kinase assays with mitotic fractionation, PIAS1 E3-mutant sumoylation assays, and double-knockout metabolic mouse models\",\n      \"pmids\": [\"23019124\", \"22977234\", \"22163316\", \"22283414\", \"22859932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect pluripotency targets partially resolved\", \"Functional consequence of mitotic redistribution on later transcription unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected NCOA3 to ubiquitin-bridge degradation, chromatin remodeling at mucin loci, EMT, and UPR signaling, linking it to cancer cell plasticity and stress responses.\",\n      \"evidence\": \"PTEN-Fbw7α bridging co-IP/ubiquitination assays, SNAI1 promoter and E-cadherin analyses, MUC4 nuclease accessibility/FUT8 assays, and XBP1-PERK-ATF4 UPR feedback experiments\",\n      \"pmids\": [\"23514585\", \"23762395\", \"25531332\", \"27109102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most mechanisms from single labs without reciprocal validation\", \"Direct vs cofactor-mediated chromatin remodeling at MUC4 not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified additional degradation regulators and a cancer stem cell function, supporting NCOA3 as a therapeutic target.\",\n      \"evidence\": \"MAD2L2/p38-dependent ubiquitination assays and tumor models; PELP1-AIB1 complex with Thr24 phospho-readout, SI-2 inhibition, and tumorsphere assays\",\n      \"pmids\": [\"29360267\", \"29348189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanisms awaiting independent confirmation\", \"Direct kinase responsible for Thr24 phosphorylation not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended NCOA3 function to immune regulation, showing a requirement for regulatory T cell induction and suppressive activity.\",\n      \"evidence\": \"Bioinformatic enrichment plus cellular loss-of-function and pharmacological inhibition with T cell suppression assays\",\n      \"pmids\": [\"33564037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets in Tregs not identified\", \"Mechanism of SRC-3 enrichment in Tregs unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dozens of competing post-translational modifications, degradation routes, and partner interactions are dynamically integrated to set NCOA3 activity in a given cellular and disease context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of PTM crosstalk\", \"Context-specific target gene programs not systematically mapped\", \"Structural basis of full-length complex assembly unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 11, 29]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 24]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 7, 25, 41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 12, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 9, 38]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [11, 22, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 13, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 19, 24, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 22, 34]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 10, 35]}\n    ],\n    \"complexes\": [\n      \"CBP/p300 coactivator complex\",\n      \"IKK complex\"\n    ],\n    \"partners\": [\n      \"ESR1\",\n      \"AR\",\n      \"EP300\",\n      \"CARM1\",\n      \"E2F1\",\n      \"ESRRB\",\n      \"ESRRA\",\n      \"PELP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}