{"gene":"RPS6KA1","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":2025,"finding":"RSK1/2 (p90 ribosomal S6 kinases, including RSK1/RPS6KA1) are activated in chemotherapy-resistant TNBC cells of both mesenchymal-like and epithelial subtypes, as measured by phospho-antibody arrays following pulse exposure and stepwise dose escalation to chemotherapy agents.","method":"Unbiased antibody arrays measuring phosphoprotein activation in chemotherapy-resistant TNBC cell populations","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method (antibody array), no pathway placement or direct mechanistic dissection of RSK1 specifically","pmids":["bio_10.1101_2025.11.01.685128"],"is_preprint":true},{"year":2025,"finding":"In Xenopus oocytes, the Mos-MAPK-Rsk1/2 pathway (including RSK1 ortholog) is required for metaphase II arrest; depletion of Greatwall kinase leads to hyperactivation of PP2A-B55, insufficient Mos accumulation, and failure of Rsk1/2 activation, thereby preventing CSF/metaphase II arrest.","method":"Greatwall kinase depletion from Xenopus oocytes with functional readouts of meiotic progression, CDK1 activity, and pathway epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Xenopus oocyte model with defined phenotypic readouts; single lab but multiple pathway-level readouts","pmids":["bio_10.1101_2025.10.03.680315"],"is_preprint":true},{"year":2025,"finding":"A substructure harboring pathogenic gain-of-function mutations in RSK1 (RPS6KA1) disrupts the protein-protein interaction between MAPK1 and RSK1, leading to MAPK1 activation and elevated expression of the immune checkpoint receptor PD-1, as identified by tiling base-editing mutagenesis screens and computational PPI disruption analysis.","method":"Base editing tiling mutagenesis screen (ProTiler-Mut computational framework) with PPI disruption analysis and PD-1 expression readout","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — functional mutagenesis screen with defined molecular readout (MAPK1-RSK1 PPI and PD-1 expression), single study","pmids":["bio_10.1101_2025.04.17.649336"],"is_preprint":true}],"current_model":"RPS6KA1 (RSK1) functions downstream of the Ras-MAPK cascade, where it interacts with MAPK1/ERK2 to become activated; gain-of-function mutations that disrupt the MAPK1-RSK1 interaction lead to aberrant MAPK1 activation and PD-1 upregulation, while in meiosis RSK1 acts downstream of Mos/MAPK to enforce metaphase II arrest, and RSK1/2 are activated in chemotherapy-resistant breast cancer cells."},"narrative":{"teleology":[{"year":2025,"claim":"The question of how RSK1 participates in meiotic cell-cycle control was addressed by showing that Mos-MAPK-Rsk1/2 pathway activation is essential for metaphase II arrest, and that upstream Greatwall kinase depletion causes PP2A-B55 hyperactivation, insufficient Mos accumulation, and failure of Rsk1 activation.","evidence":"Greatwall kinase depletion in Xenopus oocytes with functional readouts of CDK1 activity and meiotic progression (preprint)","pmids":["bio_10.1101_2025.10.03.680315"],"confidence":"Medium","gaps":["Direct substrates of RSK1 that enforce CSF arrest remain unidentified","Whether RSK1 and RSK2 have non-redundant roles in meiosis is unresolved","Findings are from a single Xenopus oocyte study; confirmation in mammalian oocytes is lacking"]},{"year":2025,"claim":"It was unknown how specific RSK1 mutations could produce gain-of-function phenotypes; tiling base-editing mutagenesis revealed that pathogenic mutations in a defined RSK1 substructure disrupt the MAPK1–RSK1 protein–protein interaction, liberating MAPK1 activity and driving PD-1 upregulation.","evidence":"Base-editing tiling mutagenesis screen with computational PPI disruption analysis and PD-1 expression readout in human cells (preprint)","pmids":["bio_10.1101_2025.04.17.649336"],"confidence":"Medium","gaps":["The structural basis of the MAPK1–RSK1 interaction disrupted by these mutations has not been resolved at atomic resolution","Whether the PD-1 upregulation is a direct transcriptional consequence of MAPK1 hyperactivation or involves additional intermediates is unknown","Independent validation of the PPI disruption by orthogonal biochemical methods (e.g., co-immunoprecipitation, SPR) has not been reported"]},{"year":2025,"claim":"RSK1/2 were identified as activated kinases in chemotherapy-resistant triple-negative breast cancer cells, raising the question of whether RSK1 functionally contributes to resistance.","evidence":"Phospho-antibody arrays in TNBC cell lines following chemotherapy dose escalation (preprint)","pmids":["bio_10.1101_2025.11.01.685128"],"confidence":"Low","gaps":["RSK1 activation was detected by a single antibody-array approach without direct mechanistic dissection of RSK1 specifically","Functional requirement of RSK1 for chemoresistance (e.g., by genetic ablation or pharmacological inhibition) was not tested","The relevant RSK1 substrates in resistant cells are unknown"]},{"year":null,"claim":"The direct substrates and downstream transcriptional programs through which RSK1 enforces meiotic arrest, regulates PD-1 expression, and potentially contributes to chemoresistance remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No systematic substrate identification for RSK1 has been reported in the timeline","Structural model of the MAPK1–RSK1 interface is lacking","In vivo physiological roles of RSK1 distinct from RSK2 have not been delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":[],"partners":["MAPK1"],"other_free_text":[]},"mechanistic_narrative":"RPS6KA1 (RSK1) is a p90 ribosomal S6 kinase that operates downstream of the Mos/MAPK cascade; in Xenopus oocytes, Rsk1 activation downstream of Mos-MAPK is required for cytostatic factor (CSF)-mediated metaphase II arrest during meiosis [bio_10.1101_2025.10.03.680315]. A gain-of-function mutational substructure in RSK1 disrupts the MAPK1–RSK1 protein–protein interaction, resulting in aberrant MAPK1 activation and upregulation of the immune checkpoint receptor PD-1 [bio_10.1101_2025.04.17.649336]."},"prefetch_data":{"uniprot":{"accession":"Q15418","full_name":"Ribosomal protein S6 kinase alpha-1","aliases":["90 kDa ribosomal protein S6 kinase 1","p90-RSK 1","p90RSK1","p90S6K","MAP kinase-activated protein kinase 1a","MAPK-activated protein kinase 1a","MAPKAP kinase 1a","MAPKAPK-1a","Ribosomal S6 kinase 1","RSK-1"],"length_aa":735,"mass_kda":82.7,"function":"Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1 (PubMed:10679322, PubMed:12213813, PubMed:15117958, PubMed:16223362, PubMed:17360704, PubMed:18722121, PubMed:26158630, PubMed:35772404, PubMed:9430688). In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes (PubMed:18508509, PubMed:18813292). In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP (PubMed:12213813, PubMed:16223362). Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity (PubMed:18508509, PubMed:18813292). Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the pre-initiation complex (PubMed:17360704). In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation (PubMed:16763566). Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway (PubMed:15342917). Also involved in feedback regulation of mTORC1 and mTORC2 by phosphorylating DEPTOR (PubMed:22017876). Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function (PubMed:10679322, PubMed:16213824). Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4) (PubMed:11684016). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB (PubMed:18508509, PubMed:18813292). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression (PubMed:18508509, PubMed:18813292). Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). In response to mTORC1 activation, phosphorylates EIF4B at 'Ser-406' and 'Ser-422' which stimulates bicarbonate cotransporter SLC4A7 mRNA translation, increasing SLC4A7 protein abundance and function (PubMed:35772404) (Microbial infection) Promotes the late transcription and translation of viral lytic genes during Kaposi's sarcoma-associated herpesvirus/HHV-8 infection, when constitutively activated","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15418/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS6KA1","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000117676","cell_line_id":"CID001261","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"CDC37","stoichiometry":0.2},{"gene":"RPS6KA3","stoichiometry":0.2},{"gene":"RPS6KA4","stoichiometry":0.2},{"gene":"TRRAP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001261","total_profiled":1310},"omim":[{"mim_id":"617517","title":"RIBOSOMAL PROTEIN S6 KINASE C1; RPS6KC1","url":"https://www.omim.org/entry/617517"},{"mim_id":"603607","title":"RIBOSOMAL PROTEIN S6 KINASE A5; RPS6KA5","url":"https://www.omim.org/entry/603607"},{"mim_id":"602006","title":"MITOGEN-ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE 2; MAPKAPK2","url":"https://www.omim.org/entry/602006"},{"mim_id":"601685","title":"RIBOSOMAL PROTEIN S6 KINASE A2; RPS6KA2","url":"https://www.omim.org/entry/601685"},{"mim_id":"601684","title":"RIBOSOMAL PROTEIN S6 KINASE A1; RPS6KA1","url":"https://www.omim.org/entry/601684"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS6KA1"},"hgnc":{"alias_symbol":["RSK1","HU-1","p90Rsk","MAPKAPK1"],"prev_symbol":[]},"alphafold":{"accession":"Q15418","domains":[{"cath_id":"3.30.200.20","chopping":"50-145_347-384","consensus_level":"medium","plddt":78.6295,"start":50,"end":384},{"cath_id":"1.10.510.10","chopping":"146-341","consensus_level":"medium","plddt":87.5619,"start":146,"end":341},{"cath_id":"3.30.200.20","chopping":"413-489","consensus_level":"high","plddt":88.4922,"start":413,"end":489},{"cath_id":"1.10.510.10","chopping":"496-707","consensus_level":"high","plddt":81.8986,"start":496,"end":707}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15418","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15418-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15418-F1-predicted_aligned_error_v6.png","plddt_mean":76.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS6KA1","jax_strain_url":"https://www.jax.org/strain/search?query=RPS6KA1"},"sequence":{"accession":"Q15418","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15418.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15418/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15418"}},"corpus_meta":[{"pmid":null,"id":"bio_10.1101_2025.11.01.685128","title":"Contribution of Mesenchymal-like and Epithelial Cellular Subsets to Chemotherapy Resistance in Triple-Negative Breast Cancer","date":"2025-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.01.685128","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.03.680315","title":"Greatwall depletion from Xenopus oocytes reveals a key role of the cyclin B/CDK1-PP2A-B55 balance in the coordination of meiotic events","date":"2025-10-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.03.680315","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.17.649336","title":"Mechanistic Insights into Proteomic Mutation-Phenotype Linkages from Tiling Mutagenesis Screens","date":"2025-04-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.17.649336","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.23.666188","title":"Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size","date":"2025-07-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.23.666188","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.27.635060","title":"Cell-state specific drug-responses are associated with differences in signaling network wiring","date":"2025-01-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.27.635060","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.16.682893","title":"Repeated COVID-19 vaccine boosters elicit variant-specific memory B cells in humans","date":"2025-10-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.682893","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.22.649918","title":"Interprotomer Crosstalk in Mosaic Viral Glycoprotein Trimers Provides Insight into Polyvalent Immunogen Co-assembly","date":"2025-04-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.22.649918","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.01.679787","title":"Memory B cell Development in Response to mRNA SARS-CoV-2 and Nanoparticle Immunization in Mice","date":"2025-10-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.01.679787","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.04.25335126","title":"Fractional versus standard BNT162b2 boosters after non-mRNA priming in Mongolia: 24-month immunogenicity and safety evidence from a randomised controlled trial","date":"2025-09-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.04.25335126","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.03.668320","title":"Integrative genomic study of mutation dynamics and Evolutionary trends in SARS-CoV-2 omicron BA.3","date":"2025-08-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.03.668320","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.22.683849","title":"Co-administration of intranasal parainfluenza virus vaccines expressing antigenically distinct SARS-CoV-2 S antigens elicits broad and durable immunity in hamsters","date":"2025-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.22.683849","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.09.25321965","title":"Immune imprinting and vaccination interval underly XBB.1.5 monovalent vaccine immunogenicity","date":"2025-02-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.09.25321965","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.29.25334703","title":"Twelve-month follow-up of immunogenicity and safety of fractional and standard booster doses of the Pfizer-BioNTech COVID-19 vaccine in adults primed with ChAdOx1, BBIBP-CorV, or GAM-CoV-Vac: a randomised controlled trial","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.29.25334703","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.18.670983","title":"Bivalent mRNA booster encoding virus-like particles elicits potent polyclass receptor-binding domain antibodies in pre-vaccinated mice","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670983","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.23.650164","title":"K5 polysaccharides inhibit SARS-CoV-2 infection by preventing spike-proteolytic priming","date":"2025-04-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.23.650164","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.11.652904","title":"Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.11.652904","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.22.634135","title":"Clonal interference and changing selective pressures shape the escape of SARS-CoV-2 from hundreds of antibodies","date":"2025-01-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.22.634135","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.17.24313789","title":"Humoral Immune Responses in German Dialysis Patients after mRNA Omicron JN.1 Vaccination","date":"2024-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.17.24313789","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.25.25324558","title":"Prospective SARS-CoV-2 Booster Vaccination in Immunosuppressant-Treated Systemic Autoimmune Disease Patients in a Randomized Controlled Trial","date":"2025-03-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.25.25324558","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.05.622148","title":"Nanoparticle-Supported, Rapid, Digital Quantification of Neutralizing Antibodies Against SARS-CoV-2 Variants","date":"2024-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.05.622148","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15344,"output_tokens":887,"usd":0.029669},"stage2":{"model":"claude-opus-4-6","input_tokens":4070,"output_tokens":1290,"usd":0.0789},"total_usd":0.108569,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"RSK1/2 (p90 ribosomal S6 kinases, including RSK1/RPS6KA1) are activated in chemotherapy-resistant TNBC cells of both mesenchymal-like and epithelial subtypes, as measured by phospho-antibody arrays following pulse exposure and stepwise dose escalation to chemotherapy agents.\",\n      \"method\": \"Unbiased antibody arrays measuring phosphoprotein activation in chemotherapy-resistant TNBC cell populations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method (antibody array), no pathway placement or direct mechanistic dissection of RSK1 specifically\",\n      \"pmids\": [\"bio_10.1101_2025.11.01.685128\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Xenopus oocytes, the Mos-MAPK-Rsk1/2 pathway (including RSK1 ortholog) is required for metaphase II arrest; depletion of Greatwall kinase leads to hyperactivation of PP2A-B55, insufficient Mos accumulation, and failure of Rsk1/2 activation, thereby preventing CSF/metaphase II arrest.\",\n      \"method\": \"Greatwall kinase depletion from Xenopus oocytes with functional readouts of meiotic progression, CDK1 activity, and pathway epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Xenopus oocyte model with defined phenotypic readouts; single lab but multiple pathway-level readouts\",\n      \"pmids\": [\"bio_10.1101_2025.10.03.680315\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A substructure harboring pathogenic gain-of-function mutations in RSK1 (RPS6KA1) disrupts the protein-protein interaction between MAPK1 and RSK1, leading to MAPK1 activation and elevated expression of the immune checkpoint receptor PD-1, as identified by tiling base-editing mutagenesis screens and computational PPI disruption analysis.\",\n      \"method\": \"Base editing tiling mutagenesis screen (ProTiler-Mut computational framework) with PPI disruption analysis and PD-1 expression readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional mutagenesis screen with defined molecular readout (MAPK1-RSK1 PPI and PD-1 expression), single study\",\n      \"pmids\": [\"bio_10.1101_2025.04.17.649336\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPS6KA1 (RSK1) functions downstream of the Ras-MAPK cascade, where it interacts with MAPK1/ERK2 to become activated; gain-of-function mutations that disrupt the MAPK1-RSK1 interaction lead to aberrant MAPK1 activation and PD-1 upregulation, while in meiosis RSK1 acts downstream of Mos/MAPK to enforce metaphase II arrest, and RSK1/2 are activated in chemotherapy-resistant breast cancer cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RPS6KA1 (RSK1) is a p90 ribosomal S6 kinase that operates downstream of the Mos/MAPK cascade; in Xenopus oocytes, Rsk1 activation downstream of Mos-MAPK is required for cytostatic factor (CSF)-mediated metaphase II arrest during meiosis [bio_10.1101_2025.10.03.680315]. A gain-of-function mutational substructure in RSK1 disrupts the MAPK1–RSK1 protein–protein interaction, resulting in aberrant MAPK1 activation and upregulation of the immune checkpoint receptor PD-1 [bio_10.1101_2025.04.17.649336].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"The question of how RSK1 participates in meiotic cell-cycle control was addressed by showing that Mos-MAPK-Rsk1/2 pathway activation is essential for metaphase II arrest, and that upstream Greatwall kinase depletion causes PP2A-B55 hyperactivation, insufficient Mos accumulation, and failure of Rsk1 activation.\",\n      \"evidence\": \"Greatwall kinase depletion in Xenopus oocytes with functional readouts of CDK1 activity and meiotic progression (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.03.680315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct substrates of RSK1 that enforce CSF arrest remain unidentified\",\n        \"Whether RSK1 and RSK2 have non-redundant roles in meiosis is unresolved\",\n        \"Findings are from a single Xenopus oocyte study; confirmation in mammalian oocytes is lacking\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"It was unknown how specific RSK1 mutations could produce gain-of-function phenotypes; tiling base-editing mutagenesis revealed that pathogenic mutations in a defined RSK1 substructure disrupt the MAPK1–RSK1 protein–protein interaction, liberating MAPK1 activity and driving PD-1 upregulation.\",\n      \"evidence\": \"Base-editing tiling mutagenesis screen with computational PPI disruption analysis and PD-1 expression readout in human cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.17.649336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The structural basis of the MAPK1–RSK1 interaction disrupted by these mutations has not been resolved at atomic resolution\",\n        \"Whether the PD-1 upregulation is a direct transcriptional consequence of MAPK1 hyperactivation or involves additional intermediates is unknown\",\n        \"Independent validation of the PPI disruption by orthogonal biochemical methods (e.g., co-immunoprecipitation, SPR) has not been reported\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RSK1/2 were identified as activated kinases in chemotherapy-resistant triple-negative breast cancer cells, raising the question of whether RSK1 functionally contributes to resistance.\",\n      \"evidence\": \"Phospho-antibody arrays in TNBC cell lines following chemotherapy dose escalation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.01.685128\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"RSK1 activation was detected by a single antibody-array approach without direct mechanistic dissection of RSK1 specifically\",\n        \"Functional requirement of RSK1 for chemoresistance (e.g., by genetic ablation or pharmacological inhibition) was not tested\",\n        \"The relevant RSK1 substrates in resistant cells are unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct substrates and downstream transcriptional programs through which RSK1 enforces meiotic arrest, regulates PD-1 expression, and potentially contributes to chemoresistance remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No systematic substrate identification for RSK1 has been reported in the timeline\",\n        \"Structural model of the MAPK1–RSK1 interface is lacking\",\n        \"In vivo physiological roles of RSK1 distinct from RSK2 have not been delineated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAPK1\"],\n    \"other_free_text\": []\n  }\n}\n```"}