Affinage

NCOA2

Nuclear receptor coactivator 2 · UniProt Q15596

Round 2 corrected
Length
1464 aa
Mass
159.2 kDa
Annotated
2026-04-29
130 papers in source corpus 57 papers cited in narrative 57 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    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

    PMID:8643509 PMID:8670870

    Open questions at the time
    • Structural basis of NR–TIF2 interaction undefined
    • Downstream effector mechanism unknown
    • Relative contribution versus other coactivators untested
  2. 1997 High

    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

    PMID:9111344 PMID:9742117

    Open questions at the time
    • No atomic-resolution structure of NR-box in complex with LBD
    • Auxiliary interaction domains not yet mapped
  3. 1998 High

    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

    PMID:9430642

    Open questions at the time
    • AD2 effector unidentified
    • Relative contributions of AD1 versus AD2 at native genes unknown
  4. 1999 High

    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

    PMID:10381882

    Open questions at the time
    • In vivo ChIP confirmation at native loci not yet performed
    • Specificity of CARM1 histone substrate in NR-regulated chromatin unclear
  5. 1999 High

    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

    PMID:10454563 PMID:9920895

    Open questions at the time
    • Structural basis of AF-1 binding unresolved
    • Whether bridging occurs simultaneously in vivo not confirmed
  6. 2001 High

    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

    PMID:11689447 PMID:12481024

    Open questions at the time
    • Identity of downstream repression effectors unknown
    • Whether the repression domain recruits HDACs or other factors untested
  7. 2002 High

    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

    PMID:12138202 PMID:12507421 PMID:15070739 PMID:17135362

    Open questions at the time
    • Cell-type-specific contributions not dissected with conditional alleles at this stage
    • Downstream target genes mediating each phenotype largely unidentified
  8. 2002 High

    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

    PMID:12060666 PMID:15347661

    Open questions at the time
    • SUMO E3 ligase(s) responsible not identified
    • Interplay between sumoylation and ubiquitination unclear
  9. 2002 High

    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

    PMID:12151000

    Open questions at the time
    • Full-length NCOA2 structure unavailable
    • How auxiliary NID and AF-1 binding surfaces are spatially arranged relative to the LxxLL-clamp unknown
  10. 2003 High

    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

    PMID:12676584 PMID:15657427

    Open questions at the time
    • Direct transcriptional targets of MOZ-TIF2 not yet genome-widely mapped
    • Whether CBP sequestration alone suffices or additional MOZ targets contribute unclear
  11. 2008 High

    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

    PMID:19039140

    Open questions at the time
    • Whether other RORα target genes contribute to the phenotype untested
    • Redundancy with SRC-1/SRC-3 in liver not fully explored
  12. 2012 High

    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

    PMID:22753499

    Open questions at the time
    • Which specific genes drive lethality not pinpointed
    • Whether pharmacological GR ligands can bypass GRIP1 requirement untested
  13. 2014 High

    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

    PMID:24529706

    Open questions at the time
    • Whether NCOA2 acetylation or phosphorylation oscillates with clock phase unknown
    • Relative contribution versus other BMAL1 coactivators not quantified
  14. 2017 High

    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

    PMID:29170386

    Open questions at the time
    • CDK9 recruitment mechanism to the complex unresolved
    • Whether other kinases contribute at different gene sets untested
  15. 2022 High

    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

    PMID:35342947

    Open questions at the time
    • In vivo tumor model with fusion expression not reported
    • Whether PI3K/AKT inhibition is curative or only cytostatic unknown
  16. 2023 High

    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

    PMID:37540802

    Open questions at the time
    • Whether NCOA2 regulates CD4+ T cell or other lymphocyte subsets similarly untested
    • Upstream signals besides CREB phosphorylation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0060090 molecular adaptor activity 5
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 12 R-HSA-1643685 Disease 8 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-4839726 Chromatin organization 2 R-HSA-9909396 Circadian clock 1
Partners
BMAL1CARM1CBPCTNNB1ESR1KLF4NR3C1PPARG
Complex memberships
GR:GRIP1:CDK9 complexMOZ-TIF2/BRPF1 complexp160/NR coactivator complex

Evidence

Reading pass · 57 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Co-immunoprecipitation, GST pulldown, yeast two-hybrid, mammalian cell transfection reporter assays, squelching assays The EMBO journal High 8670870
1996 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. Yeast two-hybrid, in vitro binding, mammalian reporter squelching assays Proceedings of the National Academy of Sciences of the United States of America High 8643509
1997 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. Yeast two-hybrid, in vitro binding, mammalian reporter assays, GR truncation/point mutant analysis Molecular and cellular biology High 9111344
1997 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. Yeast two-hybrid, mutagenesis of NR boxes, GST pulldown, mammalian two-hybrid Molecular and cellular biology High 9742117
1998 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. Mutagenesis, mammalian and yeast transfection assays, dominant-negative peptide competition The EMBO journal High 9430642
1998 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. FISH, Southern blot, RT-PCR, sequence analysis of fusion breakpoints Blood Medium 9558366
1998 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. Co-immunoprecipitation, mammalian reporter assays, promoter mutant analysis The Journal of biological chemistry Medium 9812974
1998 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. Mammalian reporter assays, ER AF-2 mutagenesis, ligand pharmacology analysis The Journal of biological chemistry Medium 9506965
1999 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. Yeast two-hybrid, co-immunoprecipitation, in vitro histone methyltransferase assay, mutagenesis, mammalian reporter assays Science High 10381882
1999 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. In vitro GST pulldown, mammalian two-hybrid, deletion and point mutagenesis The Journal of biological chemistry High 9920895
1999 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. Deletion mutagenesis, GST pulldown, mammalian reporter assays Molecular and cellular biology High 10454563
2000 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. Mammalian two-hybrid, in vitro binding, reporter assays with TIF2 mutants deficient in AF1 or AF2 interaction EMBO reports High 11265755
2001 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. Chromatin immunoprecipitation (ChIP), reporter assays, dominant-negative GRIP1 fragments, mutant analysis The EMBO journal High 11689447
2002 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. Domain mapping, Gal4-tethered reporter assays, comparative analysis of p160 family members Proceedings of the National Academy of Sciences of the United States of America High 12481024
2002 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. Genetic knockout mice, PPARγ activity assays, co-immunoprecipitation of SRC-1 and PGC-1α, thermogenesis measurements Cell High 12507421
2002 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. Gene knockout (TIF2−/− mice), histological analysis, phenotypic characterization Molecular and cellular biology High 12138202
2002 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. Site-directed mutagenesis of SUMO attachment sites, co-immunoprecipitation, confocal microscopy, reporter assays The Journal of biological chemistry High 12060666
2002 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. Immunofluorescence, live-cell imaging of nuclear foci, microinjection of GRE, confocal microscopy Biochemical and biophysical research communications Medium 15207724
2003 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. Murine bone marrow transplantation, domain deletion/mutation analysis, in vitro colony assays Cancer cell High 12676584
2002 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. X-ray crystallography of GR LBD:TIF2 peptide complex, functional validation of dimer interface mutations Cell High 12151000
2004 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. Pulse-chase, co-immunoprecipitation with ubiquitin, proteasome inhibitors (MG132, lactacystin), temperature-sensitive E1 mutant cells, GFP-GRIP1 live imaging The Journal of biological chemistry High 15347661
2005 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. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, macrophage reporter assays, IRF3-deficient and MyD88-deficient mice The EMBO journal High 16362036
2005 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. Mammalian two-hybrid, AR N/C interaction assays, point mutagenesis of GRIP1 interaction domains Biological chemistry Medium 15843149
2005 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. Co-immunoprecipitation, FRET, reporter assays, bone marrow progenitor proliferation assays, immunofluorescence Molecular and cellular biology High 15657427
2005 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. Co-immunoprecipitation, GST pulldown, point mutagenesis, mammalian reporter assays, dominant-negative peptide analysis The Journal of biological chemistry Medium 16141201
2005 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. Reporter assays, GST pulldown with MyoD deletion/point mutants, domain competition analysis The Journal of biological chemistry Medium 15563453
2005 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. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, ChIP, siRNA knockdown, reporter assays Molecular and cellular biology Medium 15988012
2006 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. Co-immunoprecipitation, siRNA knockdown, ChIP, reporter assays, immunofluorescence co-localization Molecular and cellular biology Medium 17116691
2007 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. Co-immunoprecipitation, ChIP, reporter assays, domain mapping of GRIP1–RIP140 interaction Nucleic acids research Medium 17389641
2007 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. Mammalian two-hybrid, pull-down, co-immunoprecipitation, ChIP, reporter assays, NCoR mutagenesis Biochemistry Medium 17571860
2008 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. Whole-body and conditional (liver-specific) knockout mice, reporter assays showing RORα coactivation, glucose metabolism phenotyping Science (New York, N.Y.) High 19039140
2010 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. Co-immunoprecipitation of MOZ-TIF2 with PU.1, PU.1-knockout mouse model, conditional CSF1R-suicide transgene mouse, CSF1R inhibitor treatment Nature medicine High 20418886
2010 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. Inducible, muscle-specific TIF2 conditional knockout (Cre-lox), mitochondrial respiration measurements, expression analysis Cell metabolism High 21035760
2011 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. Sleeping Beauty forward genetic screen in mice, RNAi knockdown in liver progenitor cells, chemical carcinogenesis (DEN) in Ncoa2-knockout mice Proceedings of the National Academy of Sciences of the United States of America High 22556267
2011 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. 5' RACE, RT-PCR, FISH, Affymetrix Exon array-based fusion score analysis Genes, chromosomes & cancer High 22034177
2012 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. Mass spectrometry phosphoproteomics, phosphospecific antibody generation, site-directed mutagenesis, ChIP at endogenous GR targets Molecular and cellular biology High 22158970
2012 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. Hydrogen-deuterium exchange mass spectrometry, circular dichroism, mammalian reporter assays with GR truncations The Journal of biological chemistry Medium 23132854
2012 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. Conditional knockout (Cre-lox restricted to hematopoietic cells), genome-wide RNA-seq, LPS shock model Proceedings of the National Academy of Sciences of the United States of America High 22753499
2013 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. Stable cell line generation, proliferation/motility/anchorage assays, cell cycle analysis, luciferase reporter assays, nude mouse xenografts, differentiation assays Oncogene Medium 24213582
2013 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. Co-immunoprecipitation, ChIP, shRNA knockdown, HAT-activity mutant, in vitro transformation assays International journal of hematology Medium 24258712
2014 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. Prostate-specific overexpression mouse model, PTEN-knockout combination, NCoA2 depletion in vivo, PI3K/AKT/MAPK signaling assays The Journal of clinical investigation High 25295534
2014 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. ChIP-seq (genome-wide), SRC-2 knockout mice, wheel-running behavioral assays, metabolomics, circadian gene expression analysis Cell reports High 24529706
2015 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. Metabolic flux analysis (13C-glutamine tracing), co-immunoprecipitation (SRC-2–SREBP-1), mTORC1 inhibition, murine xenograft/metastasis models, metabolic profiling of human tumor specimens The Journal of clinical investigation High 25664849
2015 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. Overexpression and knockdown of NCOA2 and LACTB2-NCOA2 fusion, Wnt pathway gene expression analysis, in vitro proliferation/invasion assays Oncogene Medium 25823027
2015 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. Co-immunoprecipitation of NcoA2 with ARNT/HIF-1α/AhR, reporter assays (HRE, XRE), siRNA knockdown, in vitro tube formation, in vivo Matrigel plug assay Toxicological sciences Medium 26350169
2016 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. Conditional macrophage-specific GRIP1 knockout (Cre-lox), IL4 stimulation assays, reporter assays, diet-induced obesity model, metabolic phenotyping Nature communications High 27464507
2017 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. Co-immunoprecipitation of GR:GRIP1:CDK9 complex, phosphospecific antibodies, ChIP-seq (genome-wide), mutagenesis of phosphorylation sites, macrophage gene expression assays Nature communications High 29170386
2021 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. Co-immunoprecipitation, phosphorylation assay (Ser487), western blot for SRC-2 phosphorylation upon PFKFB4 knockdown, transcriptome sequencing, functional cancer cell assays BMC pulmonary medicine Medium 33593309
2022 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. Co-immunoprecipitation (ETV6-NCOA2/ETV6/p300 complex), mouse bone marrow transduction/transplantation, human cord blood CD34+ transduction with xenograft, gene expression profiling Blood High 34624096
2022 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. ChIP-seq (genome-wide binding), RNA-seq (expression profiling), iPSC-MSC stable inducible expression system, phospho-AKT western blot, proliferation assays The Journal of pathology High 35342947
2023 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. 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 Cancer immunology research High 37540802
2000 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. GST pulldown, mammalian reporter assays, co-immunoprecipitation, hypoxia induction experiments Molecular and cellular biology Medium 10594042
2002 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. Mammalian reporter assays, TIF2 domain mutants, comparison of SRC-1 vs TIF2 The Journal of biological chemistry Medium 12149266
2002 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. Co-immunoprecipitation, GST pulldown (in vitro binding), reporter assays FEBS letters Medium 12208521
2004 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. Compound double-knockout mouse genetic analysis, histological characterization of testes Proceedings of the National Academy of Sciences of the United States of America High 15070739
2006 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. TIF2 knockout mice, HPA axis assays (ACTH, corticosterone), StAR and 3β-HSD expression, adrenal histology, stress response testing FASEB journal High 17135362
2011 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. High-content imaging, siRNA knockdown, phospho-PPARγ western blot, lipogenic gene expression assays The Journal of cell biology Medium 21220509

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
1997 The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 1099 9192892
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1999 Regulation of transcription by a protein methyltransferase. Science (New York, N.Y.) 991 10381882
1996 TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. The EMBO journal 904 8670870
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2002 Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 670 12151000
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proceedings of the National Academy of Sciences of the United States of America 598 8643509
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
1999 Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 543 10490106
1997 RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proceedings of the National Academy of Sciences of the United States of America 493 9238002
1997 GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Molecular and cellular biology 482 9111344
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1998 The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. The EMBO journal 430 9430642
1998 Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex. Nature 420 9590696
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2002 Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 397 11986669
2002 SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 365 12507421
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2000 Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Molecular and cellular biology 325 10594042
2001 Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities. The Journal of biological chemistry 297 11050077
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2002 T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. The Journal of biological chemistry 276 11877444
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2011 Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes, chromosomes & cancer 244 22034177
2014 Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature genetics 243 24952745
2002 Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Molecular and cellular biology 226 11971985
1998 A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 220 9558366
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2002 The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP. Molecular and cellular biology 210 12138202
1999 Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Molecular and cellular biology 208 10454563
2003 Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. The Journal of biological chemistry 205 14578343
2002 Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron 203 11931740
1999 Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. The Journal of neuroscience : the official journal of the Society for Neuroscience 195 10436050
2013 Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes, chromosomes & cancer 180 23463663
2002 Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. Proceedings of the National Academy of Sciences of the United States of America 179 12481024
2003 MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer cell 171 12676584
2005 GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nature neuroscience 166 15965473
2012 Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron 157 22325201
2001 Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. The EMBO journal 140 11689447
2008 Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science (New York, N.Y.) 136 19039140
2012 Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes. Genes, chromosomes & cancer 124 22337624
1998 SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. The Journal of biological chemistry 124 9812974
2005 The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. The EMBO journal 123 16362036
2000 Synergy between estrogen receptor alpha activation functions AF1 and AF2 mediated by transcription intermediary factor TIF2. EMBO reports 121 11265755
1998 Acute mixed lineage leukemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2. Blood 116 9731070
2002 The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. The Journal of biological chemistry 112 12060666
2005 Interactions between NEEP21, GRIP1 and GluR2 regulate sorting and recycling of the glutamate receptor subunit GluR2. The EMBO journal 93 16037816
2015 Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis. The Journal of clinical investigation 92 25664849
1998 Mechanistic principles in NR box-dependent interaction between nuclear hormone receptors and the coactivator TIF2. Molecular and cellular biology 88 9742117
2014 Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. The Journal of clinical investigation 85 25295534
1998 Enhancement of estrogen receptor transcriptional activity by the coactivator GRIP-1 highlights the role of activation function 2 in determining estrogen receptor pharmacology. The Journal of biological chemistry 85 9506965
2010 PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. Nature medicine 81 20418886
2012 Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids. Proceedings of the National Academy of Sciences of the United States of America 80 22753499
2019 Uterine Tumor Resembling Ovarian Sex Cord Tumor: A Distinct Entity Characterized by Recurrent NCOA2/3 Gene Fusions. The American journal of surgical pathology 78 30273195
2002 Crystal structure of GRIP1 PDZ6-peptide complex reveals the structural basis for class II PDZ target recognition and PDZ domain-mediated multimerization. The Journal of biological chemistry 77 12493751
2014 SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. Cell reports 69 24529706
1999 An additional region of coactivator GRIP1 required for interaction with the hormone-binding domains of a subset of nuclear receptors. The Journal of biological chemistry 69 9920895
2010 GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions. Proceedings of the National Academy of Sciences of the United States of America 67 20956289
2005 GAC63, a GRIP1-dependent nuclear receptor coactivator. Molecular and cellular biology 65 15988012
2015 GRIP1 is required for homeostatic regulation of AMPAR trafficking. Proceedings of the National Academy of Sciences of the United States of America 63 26216979
2004 cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1. The Journal of biological chemistry 63 15347661
2020 GRIP1 regulates synaptic plasticity and learning and memory. Proceedings of the National Academy of Sciences of the United States of America 60 32948689
2012 Mutations in GRIP1 cause Fraser syndrome. Journal of medical genetics 60 22510445
2010 The transcriptional coregulators TIF2 and SRC-1 regulate energy homeostasis by modulating mitochondrial respiration in skeletal muscles. Cell metabolism 60 21035760
2014 GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites. Proceedings of the National Academy of Sciences of the United States of America 59 24639525
2012 A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer. Proceedings of the National Academy of Sciences of the United States of America 59 22556267
2004 Partially redundant functions of SRC-1 and TIF2 in postnatal survival and male reproduction. Proceedings of the National Academy of Sciences of the United States of America 58 15070739
2002 Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1. Proceedings of the National Academy of Sciences of the United States of America 57 11983858
2009 Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2. Molecular cancer therapeutics 55 19240160
1997 Yeast hormone response element assays detect and characterize GRIP1 coactivator-dependent activation of transcription by thyroid and retinoid nuclear receptors. Proceedings of the National Academy of Sciences of the United States of America 50 9108040
2005 Interaction of beta-catenin and TIF2/GRIP1 in transcriptional activation by the androgen receptor. The Journal of biological chemistry 48 16141201
2015 Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade. Proceedings of the National Academy of Sciences of the United States of America 46 26109571
2005 MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function. Molecular and cellular biology 46 15657427
2004 A four PDZ domain-containing splice variant form of GRIP1 is localized in GABAergic and glutamatergic synapses in the brain. The Journal of biological chemistry 46 15226318
2018 Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney. The American journal of surgical pathology 45 30179902
2021 Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 43 33574497
2014 Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity. Cell research 42 24810301
2020 Uterine Tumor Resembling Ovarian Sex Cord Stromal Tumor (UTROSCT): A Series of 3 Cases With Extensive Rhabdoid Differentiation, Malignant Behavior, and ESR1-NCOA2 Fusions. The American journal of surgical pathology 41 32675660
1998 Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. Molecular endocrinology (Baltimore, Md.) 40 9658407
2019 The adaptor proteins HAP1a and GRIP1 collaborate to activate the kinesin-1 isoform KIF5C. Journal of cell science 39 31757889
2011 Homeostatic levels of SRC-2 and SRC-3 promote early human adipogenesis. The Journal of cell biology 38 21220509
2012 Detection of HEY1-NCOA2 fusion by fluorescence in-situ hybridization in formalin-fixed paraffin-embedded tissues as a possible diagnostic tool for mesenchymal chondrosarcoma. Pathology international 37 23252872
2016 The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis. Nature communications 36 27464507
2012 Binding of the N-terminal region of coactivator TIF2 to the intrinsically disordered AF1 domain of the glucocorticoid receptor is accompanied by conformational reorganizations. The Journal of biological chemistry 36 23132854
2005 GRIP1 in GABAergic synapses. The Journal of comparative neurology 36 15912503
2004 Association of GRIP1 with a GABA(A) receptor associated protein suggests a role for GRIP1 at inhibitory synapses. Biochemical pharmacology 36 15451408
2005 Differential use of functional domains by coiled-coil coactivator in its synergistic coactivator function with beta-catenin or GRIP1. The Journal of biological chemistry 35 16344550
2014 Chromosome aberrations and HEY1-NCOA2 fusion gene in a mesenchymal chondrosarcoma. Oncology reports 34 24839999
2007 Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1. Journal of molecular biology 34 18155042
2006 STAMP, a novel predicted factor assisting TIF2 actions in glucocorticoid receptor-mediated induction and repression. Molecular and cellular biology 34 17116691
2002 Pure antiandrogens disrupt the recruitment of coactivator GRIP1 to colocalize with androgen receptor in nuclei. FEBS letters 34 12123801
2013 Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion. International journal of hematology 33 24258712
2003 SNF2-related CBP activator protein (SRCAP) functions as a coactivator of steroid receptor-mediated transcription through synergistic interactions with CARM-1 and GRIP-1. Molecular endocrinology (Baltimore, Md.) 33 14500758
2017 Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages. Nature communications 31 29170386
2014 Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors. Human pathology 31 24856853
2002 PIAS3 (protein inhibitor of activated STAT-3) modulates the transcriptional activation mediated by the nuclear receptor coactivator TIF2. FEBS letters 30 12208521
2015 Disruption of NCOA2 by recurrent fusion with LACTB2 in colorectal cancer. Oncogene 29 25823027
2007 Amino-terminal domain of TIF2 is involved in competing for corepressor binding to glucocorticoid and progesterone receptors. Biochemistry 28 17571860
2002 TIF2 mediates the synergy between RARalpha 1 activation functions AF-1 and AF-2. The Journal of biological chemistry 27 12149266
2018 Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells. Blood 26 29371181
2014 The GRIP1/14-3-3 pathway coordinates cargo trafficking and dendrite development. Developmental cell 26 24576423
2016 Trypanosoma brucei TIF2 and TRF Suppress VSG Switching Using Overlapping and Independent Mechanisms. PloS one 25 27258069
2013 PAX3-NCOA2 fusion gene has a dual role in promoting the proliferation and inhibiting the myogenic differentiation of rhabdomyosarcoma cells. Oncogene 25 24213582
2011 Glucocorticoid-dependent phosphorylation of the transcriptional coregulator GRIP1. Molecular and cellular biology 25 22158970
2007 Orphan nuclear receptor TR2, a mediator of preadipocyte proliferation, is differentially regulated by RA through exchange of coactivator PCAF with corepressor RIP140 on a platform molecule GRIP1. Nucleic acids research 25 17389641
2006 Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 17135362
2018 Indeterminate Dendritic Cell Tumor: A Report of Two New Cases Lacking the ETV3-NCOA2 Translocation and a Literature Review. The American Journal of dermatopathology 24 29877893
2005 GRIP1 mediates the interaction between the amino- and carboxyl-termini of the androgen receptor. Biological chemistry 24 15843149
2006 MOZ-TIF2 alters cofactor recruitment and histone modification at the RARbeta2 promoter: differential effects of MOZ fusion proteins on CBP- and MOZ-dependent activators. The Journal of biological chemistry 23 16613851
2004 The genes of the coactivator TIF2 and the corepressor SMRT are primary 1alpha,25(OH)2D3 targets. The Journal of steroid biochemistry and molecular biology 23 15225781
2013 Acute BDNF treatment upregulates GluR1-SAP97 and GluR2-GRIP1 interactions: implications for sustained AMPA receptor expression. PloS one 22 23460828
2002 Regulation of GRIP1 and CBP Coactivator activity by Rho GDI modulates estrogen receptor transcriptional enhancement. The Journal of biological chemistry 22 12138084
2022 Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion: A clinicopathologic and molecular study of 13 cases with emphasis on diagnostic pitfalls. Genes, chromosomes & cancer 21 35672279
2022 A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway. Molecules (Basel, Switzerland) 21 35807406
2021 PFKFB4 promotes lung adenocarcinoma progression via phosphorylating and activating transcriptional coactivator SRC-2. BMC pulmonary medicine 21 33593309
2016 Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology. Journal of biological rhythms 21 27432117
2022 ETV6-NCOA2 fusion induces T/myeloid mixed-phenotype leukemia through transformation of nonthymic hematopoietic progenitor cells. Blood 20 34624096
2022 Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shines a light on mesenchymal chondrosarcoma tumorigenesis. The Journal of pathology 20 35342947
2015 NcoA2-Dependent Inhibition of HIF-1α Activation Is Regulated via AhR. Toxicological sciences : an official journal of the Society of Toxicology 20 26350169
2004 Nuclear structure-associated TIF2 recruits glucocorticoid receptor and its target DNA. Biochemical and biophysical research communications 20 15207724
2004 Nuclear hormone receptor coregulator GRIP1 suppresses, whereas SRC1A and p/CIP coactivate, by domain-specific binding of MyoD. The Journal of biological chemistry 20 15563453
2023 Ncoa2 Promotes CD8+ T cell-Mediated Antitumor Immunity by Stimulating T-cell Activation via Upregulation of PGC-1α Critical for Mitochondrial Function. Cancer immunology research 19 37540802
2017 GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse. Cell reports 19 28978486