Affinage

GPS1

COP9 signalosome complex subunit 1 · UniProt Q13098

Length
491 aa
Mass
55.5 kDa
Annotated
2026-06-10
46 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPS1 (CSN1/COPS1) is a component of the COP9 signalosome that couples cullin deNEDDylase activity to the control of stress signaling, DNA repair, and developmental fate specification (PMID:17276034, PMID:32384871). As a signaling effector, GPS1 enhances JNK/c-Jun kinase activity and potentiates insulin-stimulated IRS-1 serine307 phosphorylation, an activity restrained by its binding partner Asb-4, which lowers GPS1 protein levels (PMID:17276034); this JNK-activating function is repeatedly co-opted in cancer, where GPS1 is transcriptionally upregulated and drives proliferation and metastasis (PMID:30442712, PMID:37705202). In the DNA damage response, GPS1 physically interacts with the SMC5/6 kleisin subunit NSMCE4A and limits SMC5/6 accumulation at laser-induced damage sites in a manner dependent on CSN cullin deNEDDylase activity, supporting DNA end resection during homologous recombination repair (PMID:32384871). GPS1 also supports influenza virus replication by interacting with the viral M2 protein and enabling M2-dependent NF-κB activation that upregulates viral polymerase activity (PMID:31848286). Loss-of-function missense mutations in penile squamous cell carcinoma cause GPS1 to colocalize with AGO2 in cytoplasmic P-bodies and abolish miRNA-mediated gene silencing (PMID:27325650). GPS1 protein is asymmetrically partitioned between the two blastomeres of the mammalian 2-cell embryo, where its dosage influences blastocyst lineage segregation (PMID:39253500).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 Low

    Established the basic expression profile of the mammalian GPS1 homologue before any mechanistic role was known, flagging the testis as a site of regulated, stage-dependent expression.

    Evidence Differential cDNA screening, Northern blot, in situ hybridization, immunohistochemistry and Western blot across rat tissues

    PMID:9863633

    Open questions at the time
    • No functional consequence of expression assigned
    • No link to a molecular pathway
  2. 2007 Medium

    Connected GPS1 to a defined signaling output by showing it enhances JNK activity and IRS-1 ser307 phosphorylation, and is itself negatively regulated by Asb-4 at the protein level.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and overexpression kinase/phospho assays in HEK293 and NIH 3T3-L1 cells

    PMID:17276034

    Open questions at the time
    • Mechanism by which Asb-4 lowers GPS1 protein (SOCS-box-independent) not resolved
    • Direct vs indirect activation of JNK not distinguished
    • Physiological context of insulin signaling not tested in vivo
  3. 2016 Medium

    Demonstrated that cancer-derived GPS1 mutations are functional, mislocalizing GPS1 with AGO2 to P-bodies and disrupting miRNA silencing, linking GPS1 integrity to post-transcriptional gene regulation.

    Evidence Whole-exome/targeted sequencing of penile SCC plus mutant overexpression and AGO2 colocalization by confocal microscopy

    PMID:27325650

    Open questions at the time
    • Molecular basis of AGO2/P-body mislocalization unknown
    • Whether endogenous CSN deNEDDylase activity is required not tested
    • Limited mechanistic follow-up beyond colocalization
  4. 2017 Low

    Placed GPS1 within the IFT20 interactome of T cells, hinting at a role connected to immune synapse assembly, though without GPS1-specific validation.

    Evidence Quantitative mass spectrometry interactome screen in Jurkat T cells

    PMID:28154159

    Open questions at the time
    • Single MS pulldown without reciprocal or functional validation of GPS1
    • Functional consequence for GPS1 not tested
    • Interaction may be indirect within a larger complex
  5. 2018 Medium

    Showed that GPS1's JNK-activating function is harnessed in triple-negative breast cancer, where WBP2 upregulates GPS1 to drive a JNK/Jun feedback loop promoting tumor growth and migration.

    Evidence RNAi with RNA-Seq/MS, overexpression, and JNK pathway assays in MDA-MB-231 cells

    PMID:30442712

    Open questions at the time
    • Direct molecular link from GPS1 to JNK activation not biochemically resolved
    • Role of CSN deNEDDylase activity in this context untested
    • In vivo confirmation limited
  6. 2019 Medium

    Identified GPS1 as a host factor exploited by influenza virus, acting via M2 to enable NF-κB-driven enhancement of viral polymerase activity at the transcription/replication stage.

    Evidence GPS1 knockdown, stage-specific replication assays, polymerase and NF-κB reporter assays

    PMID:31848286

    Open questions at the time
    • Direct GPS1-M2 binding interface not mapped
    • How GPS1 couples M2 to NF-κB activation unresolved
    • Whether CSN deNEDDylase activity is required not tested
  7. 2020 Medium

    Defined a DNA-repair role for GPS1, showing it binds NSMCE4A and uses CSN deNEDDylase activity to limit SMC5/6 accumulation at damage sites, supporting end resection during homologous recombination.

    Evidence Yeast two-hybrid, reciprocal Co-IP, colocalization, and laser-induced damage recruitment assays with CSN inhibitor treatment

    PMID:32384871

    Open questions at the time
    • Cullin substrate(s) controlling SMC5/6 levels not identified
    • Mechanism linking SMC5/6 regulation to end resection not fully resolved
    • Single lab
  8. 2020 Low

    Implicated GPS1 in epithelial-to-amoeboid morphological plasticity in Barrett's esophagus dysplasia, with acidic (GERD-like) conditions suppressing its expression.

    Evidence siRNA high-content imaging screen, motility/morphology assays, microarray, and low-pH exposure in BE-HGD/EAC cells

    PMID:32416156

    Open questions at the time
    • Molecular pathway linking GPS1 to mesenchymal-amoeboid transition not defined
    • Limited GPS1-specific mechanistic follow-up
    • Causal vs correlative pH effect not established
  9. 2023 Low

    Showed transcriptional control of GPS1 by a LINC01305/BNC1 axis driving JNK-dependent proliferation and metastasis in esophageal squamous cell carcinoma, reinforcing GPS1 as a JNK-pathway oncogenic effector.

    Evidence ChIP/promoter assays, BNC1/GPS1 knockdown, in vitro and in vivo proliferation/metastasis assays

    PMID:37705202

    Open questions at the time
    • GPS1-to-JNK mechanistic link not directly validated beyond expression
    • Whether GPS1 acts via CSN complex unaddressed
    • Single lab
  10. 2024 Low

    Revealed a developmental role by showing asymmetric GPS1 partitioning between 2-cell-stage blastomeres dictates blastocyst lineage segregation.

    Evidence Single-cell proteomics, single-blastomere depletion/overexpression, and lineage tracing in mouse and human embryos (preprint)

    PMID:39253500

    Open questions at the time
    • Preprint, not peer-reviewed
    • Downstream effectors of GPS1 in fate specification unknown
    • Mechanism establishing asymmetric distribution unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how GPS1's CSN-associated cullin deNEDDylase activity mechanistically connects its diverse roles in JNK signaling, miRNA silencing, HRR, viral replication, and embryonic fate.
  • No unifying substrate or deNEDDylation target spanning these contexts identified
  • Direct vs CSN-complex-dependent contributions not separated for most phenotypes
  • No structural model of GPS1 within CSN provided in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
AGO2ASB4IFT20NSMCE4AWBP2
Complex memberships
COP9 signalosome

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 GPS1 (CSN1) was identified as a binding partner of Asb-4 via yeast two-hybrid screening using mouse testis and arcuate nucleus cDNA libraries; the interaction was confirmed by co-immunoprecipitation both in vitro and in HEK293 cells. GPS1 enhances c-Jun NH2-terminal kinase (JNK) activity and potentiates insulin-stimulated IRS-1 serine307 phosphorylation; co-expression of Asb-4 reduces GPS1 protein levels (independent of Asb-4's SOCS box) and inhibits JNK activity and IRS-1ser307 phosphorylation. Yeast two-hybrid screen, co-immunoprecipitation (in vitro and in HEK293 cells), overexpression/co-transfection in NIH 3T3-L1 and HEK293 cells with kinase activity assays and phospho-immunoblotting Cellular signalling Medium 17276034
2019 GPS1 (a COP9 signalosome component) interacts with influenza virus matrix protein 2 (M2) and promotes viral polymerase activity. GPS1 knockdown reduced influenza virus replication by >2 log units and impaired viral RNA transcription/replication, but did not affect viral entry, uncoating, assembly, or budding. M2 activates the NF-κB signaling pathway in a GPS1-dependent manner, and this NF-κB activation upregulates influenza virus polymerase activity. GPS1 knockdown (siRNA/shRNA), viral replication assays, reporter assays for polymerase activity and NF-κB signaling, stage-specific viral replication analyses mBio Medium 31848286
2016 GPS1 (CSN1) somatic missense mutations identified in penile squamous cell carcinoma cause loss of function; expression of GPS1 mutants in cells leads to colocalization with AGO2 in cytoplasmic P-bodies and loss of miRNA-mediated gene silencing. Whole-exome sequencing, targeted resequencing, overexpression of mutant GPS1 constructs in cells, confocal immunofluorescence colocalization with AGO2 Cancer research Medium 27325650
2020 GPS1 (CSN1) physically interacts with the SMC5/6 kleisin subunit NSMCE4A, as shown by yeast two-hybrid and confirmed by co-immunoprecipitation. GPS1 and SMC5/6 components colocalize during interphase and mitosis. Depletion of GPS1 (which negatively impacts DNA end resection during homologous recombination repair) increased SMC5/6 accumulation at sites of laser-induced DNA damage. Inhibition of CSN dennedylation activity similarly increased SMC5/6 levels at DNA damage sites, linking CSN cullin deNEDDylase activity to SMC5/6 regulation during HRR. Yeast two-hybrid, co-immunoprecipitation, confocal colocalization, GPS1 depletion with laser-induced DNA damage assay, CSN inhibitor treatment BMC molecular and cell biology Medium 32384871
2017 GPS1 (CSN1) was identified as a binding partner of IFT20 in Jurkat T cells by quantitative mass spectrometry, placing GPS1 within the IFT20 interactome relevant to immune synapse assembly and T cell receptor recycling. Quantitative mass spectrometry interactome screen in Jurkat T cells Journal of cell science Low 28154159
2018 In triple-negative breast cancer cells, WBP2 upregulates GPS1 expression, and GPS1 in turn activates the JNK/Jun signaling pathway, creating a positive feedback loop with TNIK that mediates Wnt-induced AXIN2 expression and promotes TNBC growth and migration. RNAi knockdown coupled with RNA-Seq and MS, overexpression studies, JNK pathway reporter/activity assays in MDA-MB-231 cells The Journal of biological chemistry Medium 30442712
2020 GPS1 loss-of-function (siRNA knockdown) in Barrett's esophagus high-grade dysplasia cells resulted in altered cell morphology characterized by amoeboid cellular transitions, with changes in cell motility, pseudopodia formation, and altered vimentin/E-cadherin expression, indicating a role for GPS1 in mesenchymal-amoeboid transition regulation. Low pH environments (modeling GERD) suppress GPS1 expression in BE-HGD and EAC cells but not in squamous esophageal cells. siRNA library screen with high-content imaging, functional motility/morphology assays, gene expression microarray, low pH exposure studies Cellular and molecular gastroenterology and hepatology Low 32416156
1998 The rat/mammalian fusca gene homologue (mfh), whose corresponding human sequence is GPS1, is expressed in multiple mammalian tissues with particularly strong expression in testes; testicular expression increases markedly from postnatal day 28 onwards with a stage-dependent distribution in seminiferous tubules, as shown by Northern blot, in situ hybridization, immunohistochemistry, and Western blot. Differential cDNA library screening, Northern blot, in situ hybridization, immunohistochemistry, Western blot Molecular and cellular endocrinology Low 9863633
2024 Gps1 protein is asymmetrically distributed between the two blastomeres of the mouse (and human) 2-cell embryo, with depletion or overexpression of Gps1 in one blastomere affecting lineage segregation of the resulting blastocyst, indicating a role for GPS1 in early mammalian developmental fate specification. Single-cell proteomics by mass spectrometry, microinjection-based depletion/overexpression in single blastomeres, lineage tracing in blastocysts bioRxivpreprint Low 39253500
2023 LINC01305 recruits the transcription factor BNC1 to the GPS1 promoter, upregulating GPS1 expression; elevated GPS1 then mediates activation of the JNK signaling pathway to promote proliferation and metastasis of esophageal squamous cell carcinoma cells. BNC1 knockdown inhibited ESCC proliferation and metastasis in vivo. ChIP/promoter assays showing BNC1 recruitment to GPS1 promoter, BNC1/GPS1 knockdown with in vitro and in vivo proliferation/metastasis assays, JNK pathway analysis Cancer science Low 37705202

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Structure of the Sec7 domain of the Arf exchange factor ARNO. Nature 154 9510256
2017 In vivo gibberellin gradients visualized in rapidly elongating tissues. Nature plants 145 28970478
2008 Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophrenia research 90 18678470
2005 Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins in the indoor environment. Applied and environmental microbiology 79 16269780
2016 CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma. Cancer research 54 27325650
2022 Structure of a new glycyrrhiza polysaccharide and its immunomodulatory activity. Frontiers in immunology 51 36238291
2006 Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia. Synapse (New York, N.Y.) 48 16485262
1995 CCAAT/enhancer-binding proteins alpha and beta interact with the silencer element in the promoter of glutathione S-transferase P gene during hepatocarcinogenesis. The Journal of biological chemistry 46 8537397
2013 Immune response profiling identifies autoantibodies specific to Moyamoya patients. Orphanet journal of rare diseases 43 23518061
2022 Rhamnogalacturonan-I enriched pectin from steamed ginseng ameliorates lipid metabolism in type 2 diabetic rats via gut microbiota and AMPK pathway. Journal of ethnopharmacology 42 36283638
1991 SF-B that binds to a negative element in glutathione transferase P gene is similar or identical to trans-activator LAP/IL6-DBP. Biochemical and biophysical research communications 39 1883358
2014 The combination of platelet count and neutrophil lymphocyte ratio is a predictive factor in patients with esophageal squamous cell carcinoma. Translational oncology 38 25389458
2020 Study on structure characterization of pectin from the steamed ginseng and the inhibition activity of lipid accumulation in oleic acid-induced HepG2 cells. International journal of biological macromolecules 37 32339574
2010 Elevated C-reactive protein and hypoalbuminemia measured before resection of colorectal liver metastases predict postoperative survival. Digestive surgery 37 20689289
1989 Hereditary nephritis: immunoblotting studies of the glomerular basement membrane. Laboratory investigation; a journal of technical methods and pathology 37 2654472
2013 A safeguard mechanism regulates Rho GTPases to coordinate cytokinesis with the establishment of cell polarity. PLoS biology 34 23468594
1995 Isolation of protein glycosylation mutants in the fission yeast Schizosaccharomyces pombe. Molecular biology of the cell 29 7663020
2018 Immune Responses of HLA Highly Sensitized and Nonsensitized Patients to Genetically Engineered Pig Cells. Transplantation 26 29266033
2015 Molecular signatures of sanguinarine in human pancreatic cancer cells: A large scale label-free comparative proteomics approach. Oncotarget 25 25929337
2017 The T cell IFT20 interactome reveals new players in immune synapse assembly. Journal of cell science 24 28154159
2007 Ankyrin repeat and SOCS box containing protein 4 (Asb-4) interacts with GPS1 (CSN1) and inhibits c-Jun NH2-terminal kinase activity. Cellular signalling 24 17276034
2021 Glycyrrhiza polysaccharides can improve and prolong the response of chickens to the Newcastle disease vaccine. Poultry science 23 34837761
2018 The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway. The Journal of biological chemistry 23 30442712
2020 Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair. Proceedings of the National Academy of Sciences of the United States of America 16 31964807
2019 G Protein Pathway Suppressor 1 Promotes Influenza Virus Polymerase Activity by Activating the NF-κB Signaling Pathway. mBio 13 31848286
2012 A new heterogeneous family of telomerically encoded Cryptosporidium proteins. Evolutionary applications 13 23467513
2013 Gravity Persistent Signal 1 (GPS1) reveals novel cytochrome P450s involved in gravitropism. American journal of botany 11 23284057
2024 System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening. BMC cancer 8 38937694
2021 Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes. Frontiers in physiology 8 34262479
2020 Interaction between NSMCE4A and GPS1 links the SMC5/6 complex to the COP9 signalosome. BMC molecular and cell biology 8 32384871
2018 Septin-associated proteins Aim44 and Nis1 traffic between the bud neck and the nucleus in the yeast Saccharomyces cerevisiae. Cytoskeleton (Hoboken, N.J.) 7 30341817
2017 Circulating angiotensin type II receptor: Possible marker for antibody mediated rejection after renal transplantation? Human immunology 7 28614703
2025 Gibberellin transport affects lateral root growth through HY5 in response to far-red light. The Plant cell 5 40817834
2023 LINC01305 recruits basonuclin 1 to act on G-protein pathway suppressor 1 to promote esophageal squamous cell carcinoma. Cancer science 5 37705202
2020 Ligand-Based Reactivity of Oxygenation and Alkylation in Cobalt Complexes Binding with (Thiolato)phosphine Derivatives. Inorganic chemistry 5 32186861
2020 High Content Imaging of Barrett's-Associated High-Grade Dysplasia Cells After siRNA Library Screening Reveals Acid-Responsive Regulators of Cellular Transitions. Cellular and molecular gastroenterology and hepatology 5 32416156
2017 The septin-associated kinase Gin4 recruits Gps1 to the site of cell division. Molecular biology of the cell 5 28148650
2023 A Photoactivated Ru (II) Polypyridine Complex Induced Oncotic Necrosis of A549 Cells by Activating Oxidative Phosphorylation and Inhibiting DNA Synthesis as Revealed by Quantitative Proteomics. International journal of molecular sciences 4 37175463
2024 Proteome asymmetry in mouse and human embryos before fate specification. bioRxiv : the preprint server for biology 3 39253500
2023 The orf virus 129 protein can inhibit immune responses by interacting with host complement C1q binding protein in goat turbinate bone cells. Veterinary microbiology 3 37270925
2006 Genetic variation and relationships between isolates and species of the entomopathogenic nematode genus Heterorhabditis deciphered through isozyme profiles. The Journal of parasitology 3 16883993
1998 A fusca gene homologue in mammalian tissues: Developmental regulation in the rat testes. Molecular and cellular endocrinology 3 9863633
2025 Deleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty. European journal of endocrinology 2 40193575
2026 In vitro digestion and fermentation of ginseng pectic polysaccharide GPS-1 and attenuation of its product on oleic acid-induced oxidative stress in HepG2 cells. Frontiers in pharmacology 0 41788794
2026 GPS1 Exon 9 Mutations Represent a Rare Genetic Event in Penile Squamous Cell Carcinoma Pathogenesis. International journal of molecular sciences 0 41828674
2026 Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets and DNA Methylation-Mediated Regulation in Urological Malignancies. Technology in cancer research & treatment 0 42098041

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