Affinage

GPS2

G protein pathway suppressor 2 · UniProt Q13227

Length
327 aa
Mass
36.7 kDa
Annotated
2026-06-10
45 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPS2 is a dual-function regulator that controls gene expression in the nucleus and ubiquitin-dependent signaling in the cytoplasm. As an integral subunit of the N-CoR/SMRT-HDAC3 nuclear corepressor complex, it interacts cooperatively with TBL1 at the N-CoR repression domain to form a heterotrimeric platform that restrains transcription (PMID:11931768), and it functions as a stoichiometric corepressor across diverse transcription factors governing bile acid biosynthesis, cholesterol handling, and lipid metabolism (PMID:17895379, PMID:19481530). At enhancers, the GPS2/SMRT complex sets the chromatin state by antagonizing histone demethylases—stabilizing KDM4A/JMJD2 to prime H3K9-demethylated chromatin for PPARγ binding while restraining KDM1A/LSD1 and eRNA-coupled H3K27 acetylation—so that its loss derepresses inflammatory and metabolic gene programs (PMID:24953653, PMID:33503407, PMID:36610795). Through this corepressor activity GPS2 directly represses PPARα in hepatocytes and constrains the macrophage epigenome during metabolic stress, with cell-type-specific deletion driving inflammation, steatosis, and stress hypersensitivity (PMID:27270589, PMID:30975991). In parallel, GPS2 acts non-transcriptionally as an inhibitor of the E2 enzyme Ubc13, blocking K63-linked ubiquitination of RIP1 and AKT to limit TNF-α/JNK and insulin signaling (PMID:22424771, PMID:28123943); the same activity restricts B-cell signaling and shapes nuclear-encoded mitochondrial gene expression following its regulated mitochondria-to-nucleus translocation upon depolarization (PMID:28039360, PMID:29499132). GPS2 further stabilizes partner proteins by blocking their ubiquitin-mediated degradation, protecting EKLF to sustain erythropoiesis and the LUBAC catalytic subunit HOIP to maintain NF-κB activation and vascular development (PMID:32384137, PMID:41507360). GPS2 is itself controlled post-translationally by SUMO-1 modification at K45/K71, which promotes TBL1 binding and nuclear retention, and by Siah2-mediated degradation that is countered by TBL1 and PRMT6 methylation (PMID:24943844, PMID:26070566).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 High

    Established GPS2 as a structural subunit of a defined transcriptional corepressor complex rather than a free-standing factor, anchoring all subsequent functional studies.

    Evidence Co-IP, biochemical reconstitution, and JNK reporter assays mapping GPS2-TBL1-N-CoR-HDAC3 architecture

    PMID:11931768

    Open questions at the time
    • Did not resolve atomic structure of the GPS2-TBL1-N-CoR interface
    • Mechanism of HDAC3 activation by SANT domain not linked to GPS2 directly
  2. 2001 Medium

    Early work linked GPS2 to coactivation and tumor suppressor pathways (p300, p53), framing it as a context-dependent transcriptional cofactor before its corepressor identity was consolidated.

    Evidence Co-IP, in vitro binding, reporter and cell-cycle/apoptosis assays in U2OS cells

    PMID:10846067 PMID:11486030

    Open questions at the time
    • Coactivator role not reconciled with later corepressor function
    • Whether p53/p300 effects are direct or complex-mediated unresolved
  3. 2009 High

    Defined GPS2 as a functional epigenetic regulator at specific metabolic loci, connecting corepressor occupancy to histone H3K9 demethylation and physiologic cholesterol efflux.

    Evidence RNAi, ChIP, cholesterol efflux assays, and histone methylation analysis at ABCG1; SMRT complex domain mapping; transrepression studies in LXR/SUMO-1 knockout mice

    PMID:19481530 PMID:19858209 PMID:20159957

    Open questions at the time
    • Identity of the recruited demethylase not established at this stage
    • Direct versus indirect effect on H3K9 marks unresolved
  4. 2012 High

    Revealed a wholly separate cytoplasmic function—GPS2 inhibits TRAF2/Ubc13 to restrict K63 ubiquitination of RIP1 and JNK activation—linking GPS2 to inflammation control and insulin sensitivity in vivo.

    Evidence In vitro Ubc13 enzymatic assays, ubiquitination assays, aP2-GPS2 transgenic mice, and adipocyte RNAi with inflammatory readouts

    PMID:22424771 PMID:23221346

    Open questions at the time
    • Structural basis of Ubc13 inhibition not defined
    • Nuclear/cytoplasmic pool partitioning not quantified
  5. 2014 High

    Mechanistically unified the corepressor and ubiquitin functions by showing GPS2 primes chromatin for PPARγ via ubiquitin-ligase inhibition and demethylase stabilization, and identified SUMOylation as a regulator of GPS2 stability and localization.

    Evidence ChIP-seq, ubiquitination assays, and gene expression in adipocytes; in vivo SUMOylation assays with K45R/K71R mutants and fractionation

    PMID:24943844 PMID:24953653

    Open questions at the time
    • How chromatin priming integrates with the N-CoR complex unclear
    • SUMO-1 specificity over SUMO-2/3 mechanistically unexplained
  6. 2016 High

    Cell-type-specific knockouts dissected GPS2's tissue roles, demonstrating it controls the macrophage epigenome, restrains AKT via Ubc13, and governs B-cell development and metabolic phenotypes.

    Evidence Macrophage-, adipocyte-, and B-cell-specific Gps2 knockout mice with ChIP-seq/ATAC-seq, insulin signaling, and flow cytometry

    PMID:27270589 PMID:28039360 PMID:28123943

    Open questions at the time
    • Relative contribution of nuclear versus cytoplasmic functions per tissue not separated
    • Whether obesity-with-insulin-sensitivity uncoupling generalizes beyond adipose unresolved
  7. 2018 High

    Identified mitochondria-to-nucleus retrograde signaling as a trigger that converts the cytoplasmic Ubc13-inhibitory function into a nuclear transcriptional response activating mitochondrial genes; placed GPS2 upstream of HIF1A in adipocyte remodeling.

    Evidence Live-cell imaging of translocation, ChIP, RNA Pol2 ChIP; adipocyte-specific KO with HIF1A genetic/pharmacologic epistasis

    PMID:29499132 PMID:30208320

    Open questions at the time
    • Molecular trigger and transport machinery for translocation unknown
    • Link between HIF1A and the corepressor/Ubc13 activities not defined
  8. 2019 High

    Extended corepressor function to hepatic disease, showing GPS2 directly represses PPARα and that its loss alleviates steatosis and fibrosis through lipid-catabolic gene de-repression.

    Evidence Hepatocyte-specific Gps2 knockout with integrative cistrome/epigenome/transcriptome and diet-induced NASH model

    PMID:30975991

    Open questions at the time
    • Therapeutic window of GPS2 inhibition versus inflammatory derepression not addressed
    • Human relevance limited to correlative data
  9. 2020 High

    Demonstrated GPS2 stabilizes partner transcription factors against degradation, with EKLF protection required for normal erythropoiesis, revealing a protein-stabilizing arm distinct from corepression.

    Evidence Co-IP, proteasome inhibitor and domain-mapping assays, GPS2 knockout mice with anemia, and CD34+ xenotransplantation

    PMID:32384137

    Open questions at the time
    • Whether stabilization depends on Ubc13 inhibition or a distinct mechanism unclear
    • E3 ligase targeting EKLF not identified
  10. 2021 High

    Resolved how the GPS2/SMRT complex represses enhancers, showing co-occupancy with coactivators but antagonism of eRNA-coupled H3K27 acetylation to control inflammatory gene loci.

    Evidence ChIP-seq, ATAC-seq, CRISPR editing, 4C-seq, and eRNA analysis with ob/ob adipose tissue macrophages

    PMID:33503407

    Open questions at the time
    • Mechanism that toggles complex from repressive to permissive state unresolved
    • Direct molecular target of eRNA repression not defined
  11. 2023 High

    Identified KDM1A/LSD1 antagonism as the demethylase mechanism by which GPS2/SMRT/NCOR keep repressive H3K9me2/3 marks intact at IL4-responsive enhancers, independent of STAT6.

    Evidence Genome-wide ChIP-seq, ATAC-seq, histone-mark ChIP, RNAi, and Co-IP across two macrophage models

    PMID:36610795

    Open questions at the time
    • How corepressor depletion increases KDM1A recruitment mechanistically unclear
    • Interplay with the KDM4A-stabilizing activity not reconciled
  12. 2024 Medium

    Mapped the mitochondrial Ubc13-inhibitory targets at proteome scale, showing GPS2 restrains K63 ubiquitination of outer-membrane translation factors to gate import-coupled translation and an antioxidant program.

    Evidence K63 ubiquitome mass spectrometry, GPS2 KO cells, translocation and mitochondrial translation assays

    PMID:39094987

    Open questions at the time
    • Causality between individual ubiquitination events and translation not fully established
    • Single-lab proteomic dataset awaits independent validation
  13. 2025 High

    Demonstrated GPS2 stabilizes the LUBAC catalytic subunit HOIP by blocking K48 ubiquitination, establishing an essential pro-survival/NF-κB role in endothelial cells and vascular development.

    Evidence Co-IP, site-directed mutagenesis of HOIP ubiquitination sites, EC-specific Gps2 KO mice with TNFR1 double-knockout rescue and embryonic vascular analysis

    PMID:41507360

    Open questions at the time
    • E3 ligase mediating HOIP K48 ubiquitination not identified
    • Whether HOIP stabilization is independent of Ubc13 inhibition unresolved
  14. 2025 Medium

    Extended GPS2's protein-stabilizing and corepressor roles into cancer and hematopoietic contexts, stabilizing ATF4 to drive asparaginase resistance and mediating ANKRD26-ETV6 transcriptional control in megakaryopoiesis.

    Evidence Co-IP, ubiquitination/degradation assays, xenograft model (ATF4); Co-IP and reporter assays for ANKRD26-ETV6 axis

    PMID:39791724 PMID:40693356

    Open questions at the time
    • Generality of ATF4 stabilization across tumor types untested
    • Mechanism by which GPS2 bridges ANKRD26 and ETV6 not structurally defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GPS2's nuclear corepressor function, cytoplasmic Ubc13 inhibition, and target-protein stabilization are coordinated, and what governs the partitioning and translocation between these activities, remains unresolved.
  • No structural model integrating the distinct functional modules
  • Trigger and machinery governing subcellular redistribution not defined
  • Whether protein-stabilization arm is mechanistically the same as Ubc13 inhibition unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3
Partners
ATF4EKLFHDAC3HOIPNCOR1SMRTTBL1UBE2N
Complex memberships
LUBACN-CoR/SMRT-HDAC3 corepressor complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GPS2 is an integral subunit of the N-CoR-HDAC3 nuclear receptor corepressor complex. GPS2 and TBL1 interact cooperatively with repression domain 1 of N-CoR to form a heterotrimeric structure and are indirectly linked to HDAC3 via an extended N-CoR SANT domain that also activates latent HDAC3 activity. The N-CoR-HDAC3 complex inhibits JNK activation through its associated GPS2 subunit. Co-immunoprecipitation, biochemical reconstitution, functional reporter assays Molecular cell High 11931768
2000 GPS2 (AMF-1) binds the transcriptional coactivator p300 both in vitro and in vivo, and recruits p300 into a complex with papillomavirus E2 protein, facilitating histone acetylase activity recruitment and E2-dependent transcriptional activation. In vitro binding assay, co-immunoprecipitation, co-transfection reporter assay, histone acetyltransferase immunoprecipitation Journal of virology Medium 10846067
2001 GPS2 (AMF-1) associates with p53 both in vivo and in vitro and facilitates p53-dependent transcription. Overexpression of GPS2 in U2OS cells increases basal p21(WAF1/CIP1) expression, causes G1 arrest, and increases apoptosis upon UV irradiation. Co-immunoprecipitation, in vitro binding, reporter assay, flow cytometry, cell viability assay Molecular and cellular biology Medium 11486030
2001 GPS2 interacts with HPV E6 proteins from both high- and low-risk HPV types. High-risk E6 induces degradation of GPS2 in vivo (but not in vitro) and suppresses GPS2 transcriptional activation activity. Yeast two-hybrid, co-transfection, pulse-chase analysis, transcriptional reporter assay Journal of virology Medium 11119584
2005 GPS2 interacts specifically with the hMSH4-hMSH5 heterocomplex (not with hMSH4 or hMSH5 alone), mediated through the interface of the hMSH4-hMSH5 complex and the N-terminal region of GPS2, suggesting GPS2-associated deacetylase complex functions with hMSH4-hMSH5 in homologous recombination. Co-immunoprecipitation in human cells, interaction mapping with deletion mutants, yeast two-hybrid DNA repair Medium 16122992
2007 GPS2 directly interacts with SHP, LRH-1, HNF4alpha, and FXR, acting as a differential coregulator of CYP7A1 and CYP8B1 expression in bile acid biosynthesis pathways, with GPS2 being a stoichiometric subunit of a conserved corepressor complex. Co-immunoprecipitation, ChIP, reporter assay, RNAi knockdown Proceedings of the National Academy of Sciences of the United States of America Medium 17895379
2008 GPS2 interacts with the brain-specific transcription factor RFX4_v3, co-localizes with it in the nucleus, is recruited by RFX4_v3 to the Cx3cl1 promoter, and potentiates RFX4_v3-dependent transactivation through X-box 1. GPS2 binds both the C-terminal (amino acids 575-735) and middle (amino acids 250-574) regions of RFX4_v3. Yeast two-hybrid, co-immunoprecipitation, indirect immunofluorescence, ChIP, reporter assay The Journal of biological chemistry Medium 18218630
2009 GPS2 is required for ABCG1 cholesterol transporter gene transcription and cholesterol efflux from macrophages. GPS2 facilitates LXR recruitment to an ABCG1-specific promoter/enhancer unit upon ligand activation and is functionally linked to histone H3K9 demethylation at this locus. RNAi knockdown, ChIP, cholesterol efflux assay, reporter assay, histone methylation analysis Molecular cell High 19481530
2009 GPS2 is a stable component of SMRT corepressor complexes with the repression domain mapped to the N-terminal SMRT-interacting domain. GPS2 knockdown abrogates SMRT-mediated repression; GPS2 depletion also enhanced estradiol-induced ERα target gene expression and promoted MCF-7 cell proliferation. Co-immunoprecipitation, RNAi knockdown, ChIP, reporter assay, cell proliferation assay The Journal of biological chemistry Medium 19858209
2010 GPS2 functions as a transrepression mediator connecting SUMOylated nuclear receptors (LRH-1 and LXRbeta) to the N-CoR corepressor complex at hepatic acute phase response promoters, preventing clearance of the corepressor complex upon cytokine stimulation. ChIP, Co-immunoprecipitation, reporter assay, LXR knockout mice, SUMO-1 knockout mice Genes & development High 20159957
2012 GPS2 exerts a nontranscriptional, cytoplasmic role as guardian against hyperinflammation by inhibiting TRAF2/Ubc13 enzymatic activity, thereby specifically modulating RIP1 ubiquitylation and JNK activation in the TNF-α pathway. In vivo, aP2-GPS2 transgenic mice show inhibition of TNF-α target genes in macrophages and improved insulin signaling in adipose tissue. In vitro Ubc13 enzymatic assay, co-immunoprecipitation, ubiquitination assay, transgenic mouse model, macrophage gene expression analysis Molecular cell High 22424771
2012 RNAi-mediated depletion of GPS2 from cultured human adipocytes promotes derepression of inflammatory transcription and elevation of IL-6 and MCP-1. GPS2 and SMRT expression in adipose tissue is regulated upstream by a PPARγ-TWIST1 regulatory cascade. RNAi knockdown, RT-qPCR, ELISA, ChIP, patient tissue analysis, pioglitazone treatment The Journal of clinical investigation Medium 23221346
2014 GPS2 promotes promoter-specific binding of PPARγ in adipocytes by priming chromatin through inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2. This pioneering activity is required for PPARγ-mediated regulation of ATGL and HSL lipolytic enzymes. Genome-wide ChIP-seq, co-immunoprecipitation, RNAi knockdown, ubiquitination assay, gene expression analysis in adipocytes Cell reports High 24953653
2014 GPS2 can be SUMOylated by SUMO-1 (but not SUMO-2 or -3) at K45 and K71 in the N-terminal coiled-coil domain. SUMOylation stabilizes GPS2 by promoting interaction with TBL1 and reducing ubiquitination, enhances GPS2 transcriptional suppression, and promotes GPS2 nuclear localization. Loss of SUMOylation (K45R/K71R double mutant) causes more GPS2 to appear in the cytosol. In vivo SUMOylation assay, site-directed mutagenesis, co-immunoprecipitation, subcellular fractionation, reporter assay, cell proliferation assay Molecular biology of the cell Medium 24943844
2015 GPS2 is degraded by polyubiquitination via the E3 ubiquitin ligase Siah2. Interaction with TBL1 protects GPS2 from Siah2-mediated proteasomal degradation. Methylation of GPS2 by the arginine methyltransferase PRMT6 regulates the GPS2-TBL1 interaction and inhibits proteasome-dependent degradation. Co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor experiments, methyltransferase assay The Journal of biological chemistry Medium 26070566
2016 Macrophage-specific Gps2 knockout mice show inappropriate corepressor complex function, enhancer activation, pro-inflammatory gene expression, and hypersensitivity toward metabolic-stress signals, demonstrating GPS2 controls the macrophage epigenome during activation by metabolic stress. Macrophage-specific Gps2 knockout mice, bone marrow transplantation, ChIP-seq, transcriptome analysis, ATAC-seq Nature medicine High 27270589
2016 GPS2 inhibits Ubc13-mediated K63 ubiquitination of AKT, preventing AKT activation in the insulin signaling pathway. Adipose-specific deletion of GPS2 results in sustained AKT activation, obesity under normal chow, but improved systemic insulin sensitivity due to non-inflamed adipose tissue. In vitro Ubc13 enzymatic inhibition assay, ubiquitination assay, adipo-specific GPS2 knockout mice, insulin signaling analysis Molecular metabolism High 28123943
2016 GPS2 is required to restrict TLR, BCR, and AKT/FOXO1 signaling in B cells through direct inhibition of Ubc13 enzymatic activity. B cell-targeted GPS2 deletion causes developmental defects at multiple stages of B cell differentiation. In vitro Ubc13 enzymatic inhibition assay, B cell-specific GPS2 knockout mice, flow cytometry, ubiquitination assay The Journal of biological chemistry Medium 28039360
2018 GPS2 mediates mitochondrial retrograde signaling by translocating directly from mitochondria to nucleus in response to mitochondrial depolarization. In the nucleus, GPS2 regulates histone H3K9 demethylation and RNA Pol2 activation through inhibition of Ubc13-mediated ubiquitination, activating nuclear-encoded mitochondrial genes. Live-cell imaging, subcellular fractionation, ChIP, RNA Pol2 ChIP, ubiquitination assay, adipocyte differentiation model, brown adipose tissue analysis in mice Molecular cell High 29499132
2018 GPS2 cooperates with the LPS-inducible NF-κB subunit p65 (but not LXRs or corepressor complex subunits) to activate ABCA1 expression and cholesterol efflux in macrophages upon LPS stimulation. ChIP, RNAi knockdown, cholesterol efflux assay, reporter assay in mouse and human macrophages FASEB journal Medium 30153049
2018 Adipocyte-specific GPS2 deficiency causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction driven by HIF1A activation. Pharmacological or genetic HIF1A inhibition reverses this phenotype, placing GPS2 upstream of HIF1A in adipocyte remodeling. Adipocyte-specific GPS2 knockout mice, HIF1A inhibitor treatment, genetic HIF1A deletion, transcriptome analysis, mitochondrial function assays Cell reports High 30208320
2019 GPS2, as a subunit of the NCOR-HDAC3 complex, acts as a direct repressor of PPARα in hepatocytes. Hepatocyte-specific Gps2 knockout alleviates diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes through PPARα de-repression. Hepatocyte-specific Gps2 knockout mice, integrative cistrome/epigenome/transcriptome analysis, ChIP-seq, diet-induced NASH model Nature communications High 30975991
2020 GPS2 interacts with erythroid transcription factor EKLF and prevents proteasome-mediated degradation of EKLF, thereby increasing EKLF stability and transcriptional activity. The amino acids 191-230 region of EKLF mediates GPS2 binding and is essential for EKLF stability. GPS2 knockout mice show impaired erythropoiesis and severe anemia. Co-immunoprecipitation, proteasome inhibitor assay, domain mapping by deletion mutagenesis, GPS2 knockout mice, xenotransplantation of human CD34+ cells, flow cytometry Blood High 32384137
2021 GPS2 and SMRT corepressors co-occupy candidate enhancers with coactivators CBP and MED1 but antagonistically repress eRNA transcription-coupled H3K27 acetylation. Corepressor depletion or inflammatory signaling similarly triggers enhancer activation. The GPS2/SMRT corepressor complex controls Ccl2 transcription by repressing eRNA at enhancer elements. ChIP-seq, ATAC-seq, genome editing (CRISPR), transcriptional interference, 4C-seq, eRNA analysis, ob/ob mouse adipose tissue macrophage experiments Molecular cell High 33503407
2021 GPS2 directly interacts with influenza A virus NEP protein (confirmed by GST-pulldown and co-IP). GPS2 inhibits viral RNA synthesis by reducing IAV polymerase (PB1-PB2) interaction and vRNP assembly. NEP mediates nuclear export of GPS2 and promotes its degradation, thereby overcoming GPS2-mediated inhibition of viral replication. Yeast two-hybrid, GST-pulldown, co-immunoprecipitation, GPS2 knockdown/knockout/overexpression, viral titer measurement, viral RNA synthesis assay Journal of virology Medium 33658351
2013 GPS2 directly interacts with HCV NS5A protein (domain I of NS5A and the coiled-coil domain of GPS2 mediate the interaction) and is required for NS5A association with the proviral host factor VAP-A. Knockdown of GPS2 suppresses HCV RNA replication, rescued by RNAi-resistant GPS2 re-expression. Co-immunoprecipitation in mammalian cells, mutagenesis, RNAi knockdown with rescue experiment, HCV RNA replication assay PloS one Medium 24223774
2023 GPS2 represses IL4-dependent enhancer activation in macrophages by cooperating with SMRT and NCOR to antagonize the lysine demethylase KDM1A (LSD1). Corepressor depletion increases KDM1A recruitment to enhancers, causing demethylation of repressive H3K9me2/3 marks and enhancer/gene activation independent of IL4/STAT6. Genome-wide ChIP-seq, ATAC-seq, ChIP for histone marks, RNAi knockdown, co-immunoprecipitation, macrophage IL4 stimulation assays Nucleic acids research High 36610795
2024 GPS2 inhibits K63 ubiquitination of RNA-binding and translation proteins (including PABPC1, RPS1, RACK1, eIF3M) on the outer mitochondrial membrane via Ubc13 inhibition. Removal of GPS2-mediated inhibition (by genetic deletion or stress-induced nuclear translocation) promotes import-coupled translation of nuclear-encoded mitochondrial proteins and increases expression of an adaptive antioxidant program. K63 ubiquitome profiling (mass spectrometry), GPS2 knockout cells, nuclear translocation assay, mitochondrial translation assay, protein interaction validation Pharmacological research Medium 39094987
2024 GPS2 promotes erythroid differentiation in K562 cells primarily via NCOR1; GPS2 lacking the NCOR1-binding domain fails to promote differentiation, and NCOR1 knockdown abolishes GPS2's promotive effect on hemoglobin synthesis. GPS2 overexpression/knockdown, domain deletion mutants, NCOR1 knockdown, hemin/Ara-C induced differentiation assay, benzidine staining, globin gene expression International journal of hematology Medium 38814500
2025 GPS2 binds the NZF domain of HOIP (catalytic subunit of LUBAC) and inhibits K48-linked polyubiquitination of HOIP at K579, K737, and K988, thereby preventing HOIP proteasomal degradation, maintaining LUBAC stability and NF-κB activation. EC-specific GPS2 deletion causes HOIP degradation, reduced TNF-induced NF-κB activation, increased cell-death complex-II formation, and embryonic lethality due to defective vascularization. Co-immunoprecipitation, site-directed mutagenesis of ubiquitination sites, EC-specific GPS2 knockout mice, TNFR1 double-knockout rescue, ubiquitination assay, embryonic vascular analysis Cell death and differentiation High 41507360
2025 GPS2 binds ATF4 and inhibits ubiquitin-proteasome-dependent degradation of ATF4 by impairing the interaction between ATF4 and the E3 ubiquitin ligase BTRC, thereby stabilizing ATF4 and elevating downstream ASNS expression to confer L-asparaginase resistance in ALL cells. Co-immunoprecipitation, ubiquitination assay, GPS2 knockdown/overexpression, in vitro ATF4 degradation assay, xenograft mouse model Carcinogenesis Medium 40693356
2009 GPS2 is differentially methylated at arginine within the peptide SQNPRFYHK, and this methylation state is recognized by the immune system; only the monomethylated variant induces T-cell responses. Recombinant GPS2 can be radiolabeled in vitro by arginine methyltransferase activity. 2D nano-HPLC/mass spectrometry of HLA peptidomes, ELISpot assay, in vitro radiolabeling with recombinant GPS2 FASEB journal Low 19917673
2025 GPS2, as a component of the NCoR complex, mediates the interaction between ANKRD26 and ETV6 in megakaryopoiesis; GPS2 binds both ANKRD26 and ETV6, and ANKRD26 overexpression deregulates ETV6 transcriptional repression through this GPS2-mediated axis. Co-immunoprecipitation, subcellular localization assay, reporter assay, in vitro interaction mapping Cells Medium 39791724
2025 SMRT uniquely controls the chromatin binding and nuclear localization of GPS2, NCOR, and HDAC3, acting as the chromatin anchor for the corepressor complex in macrophages. ChIP-seq, ATAC-seq, corepressor depletion (SMRT/NCOR knockdown), transcriptome analysis in RAW264.7 and BMDM cells bioRxivpreprint Low
2012 GPS2 interacts with ANKRD26, and GPS2 (along with DIPA) is normally located in the nucleus but is translocated to the cytoplasm when the C-terminus of ANKRD26 is introduced into cells. GPS2 downregulation increases adipogenesis in 3T3-L1 cells. Yeast two-hybrid, co-immunoprecipitation, subcellular localization assay, RNAi knockdown, adipogenesis assay PloS one Low 22666460

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Molecular cell 361 11931768
2010 GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response. Genes & development 155 20159957
2009 GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus. Molecular cell 104 19481530
2018 Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation. Molecular cell 97 29499132
2016 Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes. Nature medicine 78 27270589
2007 Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 75 17895379
2000 AMF-1/Gps2 binds p300 and enhances its interaction with papillomavirus E2 proteins. Journal of virology 71 10846067
2012 SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation. The Journal of clinical investigation 68 23221346
2019 Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα. Nature communications 57 30975991
2012 A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2. Molecular cell 57 22424771
2001 AMF1 (GPS2) modulates p53 transactivation. Molecular and cellular biology 49 11486030
2014 GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPARγ. Cell reports 47 24953653
2001 Gps2, a protein partner for human papillomavirus E6 proteins. Journal of virology 44 11119584
2016 Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue. Molecular metabolism 42 28123943
2021 The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages. Molecular cell 41 33503407
2018 GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation. Cell reports 40 30208320
2012 ANKRD26 and its interacting partners TRIO, GPS2, HMMR and DIPA regulate adipogenesis in 3T3-L1 cells. PloS one 30 22666460
2009 G protein pathway suppressor 2 (GPS2) is a transcriptional corepressor important for estrogen receptor alpha-mediated transcriptional regulation. The Journal of biological chemistry 29 19858209
2005 Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment. DNA repair 29 16122992
2014 SUMOylation of GPS2 protein regulates its transcription-suppressing function. Molecular biology of the cell 26 24943844
2008 G-protein pathway suppressor 2 (GPS2) interacts with the regulatory factor X4 variant 3 (RFX4_v3) and functions as a transcriptional co-activator. The Journal of biological chemistry 26 18218630
2016 Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development. The Journal of biological chemistry 22 28039360
2015 Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation. The Journal of biological chemistry 21 26070566
2020 GPS2 promotes erythroid differentiation by control of the stability of EKLF protein. Blood 17 32384137
2016 G protein pathway suppressor 2 (GPS2) acts as a tumor suppressor in liposarcoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 27460081
2022 Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma. The Journal of pathology 15 35049062
2014 Identification of an MLL4-GPS2 fusion as an oncogenic driver of undifferentiated spindle cell sarcoma in a child. Genes, chromosomes & cancer 15 25139254
2018 G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide-induced ATP-binding cassette transporter A1 expression in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 30153049
2020 Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion. Cell reports 12 32937117
2023 Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4. Nucleic acids research 10 36610795
2021 Interaction of NEP with G Protein Pathway Suppressor 2 Facilitates Influenza A Virus Replication by Weakening the Inhibition of GPS2 to RNA Synthesis and Ribonucleoprotein Assembly. Journal of virology 10 33658351
2009 Differential arginine methylation of the G-protein pathway suppressor GPS-2 recognized by tumor-specific T cells in melanoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 19917673
2023 GPS2-mediated regulation of the adipocyte secretome modulates adipose tissue remodeling at the onset of diet-induced obesity. Molecular metabolism 9 36731652
2024 GPS2 ameliorates cigarette smoking-induced pulmonary vascular remodeling by modulating the ras-Raf-ERK axis. Respiratory research 7 38755610
2025 Liquid-liquid phase separation of GPS2-LATS1 promotes colorectal cancer progression by reprogramming lipid metabolism. Oncogene 6 40715488
2024 Inhibition of K63 ubiquitination by G-Protein pathway suppressor 2 (GPS2) regulates mitochondria-associated translation. Pharmacological research 5 39094987
2024 Regulation mechanism of GPS2 on PGC-1α/Drp1-mediated mitochondrial dynamics in inflammation of acute lung injury. International immunopharmacology 5 39116501
2013 GPS2 is required for the association of NS5A with VAP-A and hepatitis C virus replication. PloS one 5 24223774
2025 GPS2 confers l-asparaginase resistance in acute lymphoblastic leukemia cells through ATF4/ASNS axis. Carcinogenesis 4 40693356
2014 Knockdown of a novel G-protein pathway suppressor 2 (GPS2) leads to shrimp mortality by exuvial entrapment during ecdysis. Fish & shellfish immunology 3 24434648
2024 GPS2 promotes erythroid differentiation in K562 erythroleukemia cells primarily via NCOR1. International journal of hematology 2 38814500
2023 DHA-Provoked Reduction in Adipogenesis and Glucose Uptake Could Be Mediated by Gps2 Upregulation in Immature 3T3-L1 Cells. International journal of molecular sciences 2 37686130
2026 GPS2 regulates embryonic angiogenesis by enhancing endothelial cell survival through stabilizing HOIP. Cell death and differentiation 1 41507360
2025 The SIRT1/GPS2/AIP1 axis regulates pulmonary vascular permeability in ventilator-induced lung injury. Molecular and cellular biochemistry 1 40397290
2024 Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6. Cells 0 39791724

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