{"gene":"GPS1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"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","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirmed interaction; kinase activity and phosphorylation assays with overexpression; single lab, two orthogonal methods","pmids":["17276034"],"is_preprint":false},{"year":2019,"finding":"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.","method":"GPS1 knockdown (siRNA/shRNA), viral replication assays, reporter assays for polymerase activity and NF-κB signaling, stage-specific viral replication analyses","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined viral phenotype, multiple orthogonal assays (replication, polymerase, NF-κB), single lab","pmids":["31848286"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Whole-exome sequencing, targeted resequencing, overexpression of mutant GPS1 constructs in cells, confocal immunofluorescence colocalization with AGO2","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional cell-based experiment with mutant constructs and colocalization; single lab, limited mechanistic follow-up detail in abstract","pmids":["27325650"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal colocalization, GPS1 depletion with laser-induced DNA damage assay, CSN inhibitor treatment","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP confirms interaction; functional laser-damage recruitment assay; single lab, multiple orthogonal methods","pmids":["32384871"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Quantitative mass spectrometry interactome screen in Jurkat T cells","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single MS-based pulldown identification, no direct functional validation of GPS1 specifically; pan-interactome screen context","pmids":["28154159"],"is_preprint":false},{"year":2018,"finding":"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.","method":"RNAi knockdown coupled with RNA-Seq and MS, overexpression studies, JNK pathway reporter/activity assays in MDA-MB-231 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi plus MS/RNA-Seq multi-omics, functional pathway assays; single lab, two orthogonal methods","pmids":["30442712"],"is_preprint":false},{"year":2020,"finding":"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.","method":"siRNA library screen with high-content imaging, functional motility/morphology assays, gene expression microarray, low pH exposure studies","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA phenotypic screen with morphological readout; limited mechanistic follow-up on GPS1 specifically; single lab","pmids":["32416156"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Differential cDNA library screening, Northern blot, in situ hybridization, immunohistochemistry, Western blot","journal":"Molecular and cellular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization/expression study without direct functional mechanistic follow-up; single lab","pmids":["9863633"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Single-cell proteomics by mass spectrometry, microinjection-based depletion/overexpression in single blastomeres, lineage tracing in blastocysts","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — functional blastomere manipulation with lineage readout; preprint, single lab, limited mechanistic pathway placement","pmids":["39253500"],"is_preprint":true},{"year":2023,"finding":"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.","method":"ChIP/promoter assays showing BNC1 recruitment to GPS1 promoter, BNC1/GPS1 knockdown with in vitro and in vivo proliferation/metastasis assays, JNK pathway analysis","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — promoter recruitment and knockdown phenotype; mechanistic detail of GPS1-JNK link not directly validated in this study beyond expression; single lab","pmids":["37705202"],"is_preprint":false}],"current_model":"GPS1 (also known as COPS1/CSN1) is a component of the COP9 signalosome (CSN) with cullin deNEDDylase activity; it physically interacts with partners including Asb-4, NSMCE4A (SMC5/6 complex), and influenza M2 protein, and mechanistically promotes JNK/c-Jun signaling, supports influenza viral polymerase activity via NF-κB pathway activation in a M2-dependent manner, regulates homologous recombination repair by modulating SMC5/6 recruitment to DNA damage sites, and is required for early mammalian embryo lineage segregation, with loss-of-function mutations in certain cancer contexts disrupting miRNA-mediated gene silencing through AGO2/P-body mislocalization."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9863633"],"confidence":"Low","gaps":["No functional consequence of expression assigned","No link to a molecular pathway"]},{"year":2007,"claim":"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","pmids":["17276034"],"confidence":"Medium","gaps":["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"]},{"year":2016,"claim":"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","pmids":["27325650"],"confidence":"Medium","gaps":["Molecular basis of AGO2/P-body mislocalization unknown","Whether endogenous CSN deNEDDylase activity is required not tested","Limited mechanistic follow-up beyond colocalization"]},{"year":2017,"claim":"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","pmids":["28154159"],"confidence":"Low","gaps":["Single MS pulldown without reciprocal or functional validation of GPS1","Functional consequence for GPS1 not tested","Interaction may be indirect within a larger complex"]},{"year":2018,"claim":"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","pmids":["30442712"],"confidence":"Medium","gaps":["Direct molecular link from GPS1 to JNK activation not biochemically resolved","Role of CSN deNEDDylase activity in this context untested","In vivo confirmation limited"]},{"year":2019,"claim":"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","pmids":["31848286"],"confidence":"Medium","gaps":["Direct GPS1-M2 binding interface not mapped","How GPS1 couples M2 to NF-κB activation unresolved","Whether CSN deNEDDylase activity is required not tested"]},{"year":2020,"claim":"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","pmids":["32384871"],"confidence":"Medium","gaps":["Cullin substrate(s) controlling SMC5/6 levels not identified","Mechanism linking SMC5/6 regulation to end resection not fully resolved","Single lab"]},{"year":2020,"claim":"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","pmids":["32416156"],"confidence":"Low","gaps":["Molecular pathway linking GPS1 to mesenchymal-amoeboid transition not defined","Limited GPS1-specific mechanistic follow-up","Causal vs correlative pH effect not established"]},{"year":2023,"claim":"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","pmids":["37705202"],"confidence":"Low","gaps":["GPS1-to-JNK mechanistic link not directly validated beyond expression","Whether GPS1 acts via CSN complex unaddressed","Single lab"]},{"year":2024,"claim":"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)","pmids":["39253500"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Downstream effectors of GPS1 in fate specification unknown","Mechanism establishing asymmetric distribution unresolved"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]}],"complexes":["COP9 signalosome"],"partners":["ASB4","NSMCE4A","AGO2","WBP2","IFT20"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13098","full_name":"COP9 signalosome complex subunit 1","aliases":["G protein pathway suppressor 1","GPS-1","JAB1-containing signalosome subunit 1","Protein MFH"],"length_aa":491,"mass_kda":55.5,"function":"Essential component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Suppresses G-protein- and mitogen-activated protein kinase-mediated signal transduction","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13098/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GPS1","classification":"Common Essential","n_dependent_lines":1188,"n_total_lines":1208,"dependency_fraction":0.9834437086092715},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDB1","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GPS1","total_profiled":1310},"omim":[{"mim_id":"616008","title":"COP9 SIGNALOSOME, SUBUNIT 4; COPS4","url":"https://www.omim.org/entry/616008"},{"mim_id":"604850","title":"COP9 SIGNALOSOME, SUBUNIT 5; COPS5","url":"https://www.omim.org/entry/604850"},{"mim_id":"604665","title":"COP9 SIGNALOSOME, SUBUNIT 3; COPS3","url":"https://www.omim.org/entry/604665"},{"mim_id":"604508","title":"COP9 SIGNALOSOME, SUBUNIT 2; COPS2","url":"https://www.omim.org/entry/604508"},{"mim_id":"603134","title":"CULLIN 1; CUL1","url":"https://www.omim.org/entry/603134"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GPS1"},"hgnc":{"alias_symbol":["COPS1","CSN1"],"prev_symbol":[]},"alphafold":{"accession":"Q13098","domains":[{"cath_id":"1.10.10","chopping":"383-453","consensus_level":"medium","plddt":92.851,"start":383,"end":453}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13098","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13098-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13098-F1-predicted_aligned_error_v6.png","plddt_mean":84.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPS1","jax_strain_url":"https://www.jax.org/strain/search?query=GPS1"},"sequence":{"accession":"Q13098","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13098.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13098/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13098"}},"corpus_meta":[{"pmid":"9510256","id":"PMC_9510256","title":"Structure of the Sec7 domain of the 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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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirmed interaction; kinase activity and phosphorylation assays with overexpression; single lab, two orthogonal methods\",\n      \"pmids\": [\"17276034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"GPS1 knockdown (siRNA/shRNA), viral replication assays, reporter assays for polymerase activity and NF-κB signaling, stage-specific viral replication analyses\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined viral phenotype, multiple orthogonal assays (replication, polymerase, NF-κB), single lab\",\n      \"pmids\": [\"31848286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, targeted resequencing, overexpression of mutant GPS1 constructs in cells, confocal immunofluorescence colocalization with AGO2\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional cell-based experiment with mutant constructs and colocalization; single lab, limited mechanistic follow-up detail in abstract\",\n      \"pmids\": [\"27325650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal colocalization, GPS1 depletion with laser-induced DNA damage assay, CSN inhibitor treatment\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP confirms interaction; functional laser-damage recruitment assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32384871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative mass spectrometry interactome screen in Jurkat T cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single MS-based pulldown identification, no direct functional validation of GPS1 specifically; pan-interactome screen context\",\n      \"pmids\": [\"28154159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown coupled with RNA-Seq and MS, overexpression studies, JNK pathway reporter/activity assays in MDA-MB-231 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi plus MS/RNA-Seq multi-omics, functional pathway assays; single lab, two orthogonal methods\",\n      \"pmids\": [\"30442712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA library screen with high-content imaging, functional motility/morphology assays, gene expression microarray, low pH exposure studies\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA phenotypic screen with morphological readout; limited mechanistic follow-up on GPS1 specifically; single lab\",\n      \"pmids\": [\"32416156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Differential cDNA library screening, Northern blot, in situ hybridization, immunohistochemistry, Western blot\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization/expression study without direct functional mechanistic follow-up; single lab\",\n      \"pmids\": [\"9863633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell proteomics by mass spectrometry, microinjection-based depletion/overexpression in single blastomeres, lineage tracing in blastocysts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional blastomere manipulation with lineage readout; preprint, single lab, limited mechanistic pathway placement\",\n      \"pmids\": [\"39253500\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP/promoter assays showing BNC1 recruitment to GPS1 promoter, BNC1/GPS1 knockdown with in vitro and in vivo proliferation/metastasis assays, JNK pathway analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — promoter recruitment and knockdown phenotype; mechanistic detail of GPS1-JNK link not directly validated in this study beyond expression; single lab\",\n      \"pmids\": [\"37705202\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPS1 (also known as COPS1/CSN1) is a component of the COP9 signalosome (CSN) with cullin deNEDDylase activity; it physically interacts with partners including Asb-4, NSMCE4A (SMC5/6 complex), and influenza M2 protein, and mechanistically promotes JNK/c-Jun signaling, supports influenza viral polymerase activity via NF-κB pathway activation in a M2-dependent manner, regulates homologous recombination repair by modulating SMC5/6 recruitment to DNA damage sites, and is required for early mammalian embryo lineage segregation, with loss-of-function mutations in certain cancer contexts disrupting miRNA-mediated gene silencing through AGO2/P-body mislocalization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3]. 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 [#0]; this JNK-activating function is repeatedly co-opted in cancer, where GPS1 is transcriptionally upregulated and drives proliferation and metastasis [#5, #9]. 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 [#3]. GPS1 also supports influenza virus replication by interacting with the viral M2 protein and enabling M2-dependent NF-\\u03baB activation that upregulates viral polymerase activity [#1]. 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 [#2]. GPS1 protein is asymmetrically partitioned between the two blastomeres of the mammalian 2-cell embryo, where its dosage influences blastocyst lineage segregation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"Differential cDNA screening, Northern blot, in situ hybridization, immunohistochemistry and Western blot across rat tissues\",\n      \"pmids\": [\"9863633\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence of expression assigned\", \"No link to a molecular pathway\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, and overexpression kinase/phospho assays in HEK293 and NIH 3T3-L1 cells\",\n      \"pmids\": [\"17276034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-exome/targeted sequencing of penile SCC plus mutant overexpression and AGO2 colocalization by confocal microscopy\",\n      \"pmids\": [\"27325650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of AGO2/P-body mislocalization unknown\", \"Whether endogenous CSN deNEDDylase activity is required not tested\", \"Limited mechanistic follow-up beyond colocalization\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed GPS1 within the IFT20 interactome of T cells, hinting at a role connected to immune synapse assembly, though without GPS1-specific validation.\",\n      \"evidence\": \"Quantitative mass spectrometry interactome screen in Jurkat T cells\",\n      \"pmids\": [\"28154159\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single MS pulldown without reciprocal or functional validation of GPS1\", \"Functional consequence for GPS1 not tested\", \"Interaction may be indirect within a larger complex\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi with RNA-Seq/MS, overexpression, and JNK pathway assays in MDA-MB-231 cells\",\n      \"pmids\": [\"30442712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from GPS1 to JNK activation not biochemically resolved\", \"Role of CSN deNEDDylase activity in this context untested\", \"In vivo confirmation limited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified GPS1 as a host factor exploited by influenza virus, acting via M2 to enable NF-\\u03baB-driven enhancement of viral polymerase activity at the transcription/replication stage.\",\n      \"evidence\": \"GPS1 knockdown, stage-specific replication assays, polymerase and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"31848286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GPS1-M2 binding interface not mapped\", \"How GPS1 couples M2 to NF-\\u03baB activation unresolved\", \"Whether CSN deNEDDylase activity is required not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, colocalization, and laser-induced damage recruitment assays with CSN inhibitor treatment\",\n      \"pmids\": [\"32384871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cullin substrate(s) controlling SMC5/6 levels not identified\", \"Mechanism linking SMC5/6 regulation to end resection not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated GPS1 in epithelial-to-amoeboid morphological plasticity in Barrett's esophagus dysplasia, with acidic (GERD-like) conditions suppressing its expression.\",\n      \"evidence\": \"siRNA high-content imaging screen, motility/morphology assays, microarray, and low-pH exposure in BE-HGD/EAC cells\",\n      \"pmids\": [\"32416156\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Molecular pathway linking GPS1 to mesenchymal-amoeboid transition not defined\", \"Limited GPS1-specific mechanistic follow-up\", \"Causal vs correlative pH effect not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP/promoter assays, BNC1/GPS1 knockdown, in vitro and in vivo proliferation/metastasis assays\",\n      \"pmids\": [\"37705202\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"GPS1-to-JNK mechanistic link not directly validated beyond expression\", \"Whether GPS1 acts via CSN complex unaddressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a developmental role by showing asymmetric GPS1 partitioning between 2-cell-stage blastomeres dictates blastocyst lineage segregation.\",\n      \"evidence\": \"Single-cell proteomics, single-blastomere depletion/overexpression, and lineage tracing in mouse and human embryos (preprint)\",\n      \"pmids\": [\"39253500\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Downstream effectors of GPS1 in fate specification unknown\", \"Mechanism establishing asymmetric distribution unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"COP9 signalosome\"],\n    \"partners\": [\"ASB4\", \"NSMCE4A\", \"AGO2\", \"WBP2\", \"IFT20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}