{"gene":"RPS6KB2","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2025,"finding":"USF1 transcription factor activates RPS6KB2 expression by directly binding to its promoter region; RPS6KB2 knockdown reduces cell proliferation, migration, and tumor growth while promoting apoptosis, and these effects are rescued by the AKT activator SC79, placing RPS6KB2 upstream of the AKT/HDM2/p53 signaling pathway in B-cell non-Hodgkin lymphoma.","method":"Bioinformatics promoter analysis, RT-qPCR, immunohistochemistry, western blot, siRNA knockdown, AKT activator rescue (SC79), functional proliferation/migration/apoptosis assays","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue and pathway placement by single lab using multiple orthogonal methods, but no in vitro reconstitution or structural validation","pmids":["40886264"],"is_preprint":false},{"year":2024,"finding":"RPS6KB2 knockdown in hepatocellular carcinoma cells reduces cell proliferation, invasion, and migration, and upregulates proinflammatory cytokines (as measured by Bax, Bcl-2, MMP2, MMP9, PCNA expression changes), supporting a role for RPS6KB2 in cancer cell survival and immune modulation.","method":"siRNA knockdown, EDU cell proliferation assay, wound healing assay, Transwell invasion assay, western blot for apoptosis/migration markers and proinflammatory factors","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single KD approach with phenotypic readouts but limited pathway mechanistic detail","pmids":["38281249"],"is_preprint":false},{"year":2017,"finding":"In Chinese tongue sole (Cynoglossus semilaevis), rps6kb2 (an AGC kinase family member orthologous to mammalian RPS6KB2) maps to a metamorphosis-related quantitative trait locus; its expression peaks at metamorphic climax stage and is distributed in all tissues undergoing transformation (tail, jaw, eye, skin), suggesting a general role in tissue transformation during flatfish metamorphosis.","method":"Genetic linkage mapping, quantitative RT-PCR, whole-mount in situ hybridization","journal":"Marine biotechnology (New York, N.Y.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, expression-based localization in a fish ortholog, no direct functional manipulation of the protein","pmids":["28779262"],"is_preprint":false},{"year":2025,"finding":"In a lncRNA regulatory circuit, downregulation of CyKILRb causes loss of RPS6KB2 expression along with PIK3R2 and GNB2, while CyKILRb ectopic expression has the opposite effect, placing RPS6KB2 as a downstream effector of the CyKILRb→PIK3R2→PI3K→AKT axis in tumor promotion.","method":"Deep RNA sequencing, siRNA knockdown of CyKILRb, ectopic overexpression, PI3K/AKT inhibitor treatment, cell proliferation and clonogenic survival assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, RPS6KB2 is a downstream readout gene rather than the direct experimental target; no direct mechanistic manipulation of RPS6KB2 itself","pmids":["bio_10.1101_2025.10.13.682173"],"is_preprint":true}],"current_model":"RPS6KB2 (S6K2/p70S6Kβ) functions as a downstream effector of the AKT/mTORC1 signaling axis, where its transcription is activated by USF1 binding to its promoter, and its kinase activity promotes cell proliferation, survival, and migration through the AKT/HDM2/p53 pathway; its expression is also regulated downstream of a CyKILRb→PIK3R2→PI3K→AKT feed-forward circuit, and knockdown in cancer cells reduces proliferation and migration while enhancing proinflammatory cytokine secretion."},"narrative":{"mechanistic_narrative":"RPS6KB2 (S6K2) is a kinase that acts as a pro-tumorigenic effector within PI3K/AKT signaling, where its expression and activity promote cancer cell proliferation, migration, and survival [PMID:40886264, PMID:38281249]. In B-cell non-Hodgkin lymphoma, its transcription is directly activated by the transcription factor USF1 binding to its promoter, and its loss is rescued by AKT activation, placing RPS6KB2 upstream of the AKT/HDM2/p53 axis; knockdown reduces proliferation, migration, and tumor growth while promoting apoptosis [PMID:40886264]. Consistent functional dependencies are observed in hepatocellular carcinoma, where knockdown suppresses proliferation, invasion, and migration and alters apoptotic (Bax/Bcl-2) and matrix-remodeling (MMP2/MMP9) markers while enhancing proinflammatory cytokine output [PMID:38281249]. Beyond these phenotypic and transcriptional-regulatory observations, no direct biochemical characterization of RPS6KB2 substrates, catalytic mechanism, or structure is present in the available corpus.","teleology":[{"year":2017,"claim":"Established that rps6kb2 expression correlates spatiotemporally with active tissue transformation, providing the first developmental-context association for the gene.","evidence":"Genetic linkage mapping, qRT-PCR, and in situ hybridization in a Chinese tongue sole ortholog","pmids":["28779262"],"confidence":"Low","gaps":["Expression-only association in a fish ortholog with no functional manipulation","No demonstration of a causal role in metamorphosis","No connection to a defined signaling pathway"]},{"year":2024,"claim":"Showed that RPS6KB2 is functionally required for cancer cell proliferation, invasion, and migration, framing it as a survival/migration driver rather than a passive marker.","evidence":"siRNA knockdown with EdU, wound-healing, Transwell, and apoptosis/migration marker western blots in hepatocellular carcinoma cells","pmids":["38281249"],"confidence":"Low","gaps":["Single knockdown approach with phenotypic readouts only","No direct mechanistic pathway linkage","Marker changes do not establish direct substrates or upstream regulators"]},{"year":2025,"claim":"Defined how RPS6KB2 is transcriptionally controlled and where it sits in oncogenic signaling, linking USF1-driven expression to the AKT/HDM2/p53 axis.","evidence":"Promoter analysis, RT-qPCR, IHC, siRNA knockdown, and AKT-activator (SC79) rescue with proliferation/migration/apoptosis assays in B-cell non-Hodgkin lymphoma","pmids":["40886264"],"confidence":"Medium","gaps":["No in vitro reconstitution of the USF1–promoter interaction beyond binding inference","Connection to HDM2/p53 inferred from rescue rather than direct biochemistry","Kinase substrates mediating the phenotype not identified"]},{"year":2025,"claim":"Placed RPS6KB2 as a downstream readout of a lncRNA-controlled PI3K/AKT feed-forward circuit, expanding its upstream regulatory context.","evidence":"RNA-seq, CyKILRb knockdown/overexpression, and PI3K/AKT inhibitor treatment with proliferation and clonogenic assays (preprint)","pmids":["bio_10.1101_2025.10.13.682173"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","RPS6KB2 measured as a downstream readout without direct manipulation","Mechanism linking CyKILRb/PIK3R2 to RPS6KB2 expression unresolved"]},{"year":null,"claim":"The direct biochemical activity of RPS6KB2 — its kinase substrates, catalytic regulation, and structural basis — remains uncharacterized in this corpus.","evidence":"No discovery directly assays RPS6KB2 enzymatic activity or substrate phosphorylation","pmids":[],"confidence":"Low","gaps":["No substrate identified","No structural or biochemical kinase characterization","Pathway placement rests on rescue/correlative rather than direct enzymatic evidence"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBS0","full_name":"Ribosomal protein S6 kinase beta-2","aliases":["70 kDa ribosomal protein S6 kinase 2","P70S6K2","p70-S6K 2","S6 kinase-related kinase","SRK","Serine/threonine-protein kinase 14B","p70 ribosomal S6 kinase beta","S6K-beta","p70 S6 kinase beta","p70 S6K-beta","p70 S6KB","p70-beta"],"length_aa":482,"mass_kda":53.5,"function":"Phosphorylates specifically ribosomal protein S6 (PubMed:29750193). Seems to act downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression in an alternative pathway regulated by MEAK7 (PubMed:29750193)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UBS0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS6KB2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMA16","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/RPS6KB2","total_profiled":1310},"omim":[{"mim_id":"619331","title":"MTOR-ASSOCIATED PROTEIN, EAK7 HOMOLOG; MEAK7","url":"https://www.omim.org/entry/619331"},{"mim_id":"611520","title":"POLYMERASE DELTA-INTERACTING PROTEIN 3; POLDIP3","url":"https://www.omim.org/entry/611520"},{"mim_id":"608939","title":"RIBOSOMAL PROTEIN S6 KINASE B2; RPS6KB2","url":"https://www.omim.org/entry/608939"},{"mim_id":"608938","title":"RIBOSOMAL PROTEIN S6 KINASE B1; RPS6KB1","url":"https://www.omim.org/entry/608938"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS6KB2"},"hgnc":{"alias_symbol":["p70S6Kb","P70-BETA","STK14B","KLS","S6KB","S6Kbeta","S6Kβ"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBS0","domains":[{"cath_id":"3.30.200.20","chopping":"62-153_351-403","consensus_level":"medium","plddt":86.6679,"start":62,"end":403},{"cath_id":"1.10.510.10","chopping":"156-349","consensus_level":"medium","plddt":91.9227,"start":156,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBS0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBS0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBS0-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS6KB2","jax_strain_url":"https://www.jax.org/strain/search?query=RPS6KB2"},"sequence":{"accession":"Q9UBS0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBS0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBS0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBS0"}},"corpus_meta":[{"pmid":"21035469","id":"PMC_21035469","title":"Genetic variation in RPS6KA1, RPS6KA2, RPS6KB1, RPS6KB2, and PDK1 and risk of colon or rectal cancer.","date":"2010","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/21035469","citation_count":46,"is_preprint":false},{"pmid":"34705606","id":"PMC_34705606","title":"NSUN6, an RNA methyltransferase of 5-mC controls glioblastoma response to temozolomide (TMZ) via NELFB and RPS6KB2 interaction.","date":"2021","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34705606","citation_count":32,"is_preprint":false},{"pmid":"37236108","id":"PMC_37236108","title":"Biodegradation of p-hydroxybenzoic acid in Herbaspirillum aquaticum KLS-1 isolated from tailing soil: Characterization and molecular mechanism.","date":"2023","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/37236108","citation_count":17,"is_preprint":false},{"pmid":"35779192","id":"PMC_35779192","title":"Anti-Inflammatory Properties of KLS-13019: a Novel GPR55 Antagonist for Dorsal Root Ganglion and Hippocampal Cultures.","date":"2022","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/35779192","citation_count":11,"is_preprint":false},{"pmid":"39134424","id":"PMC_39134424","title":"KLS-13019, a Novel Structural Analogue of Cannabidiol and GPR55 Receptor Antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy in Rats.","date":"2024","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39134424","citation_count":7,"is_preprint":false},{"pmid":"37273920","id":"PMC_37273920","title":"Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer.","date":"2023","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/37273920","citation_count":3,"is_preprint":false},{"pmid":"37160694","id":"PMC_37160694","title":"Potential inhibitors of RPS6KB2 and NRF2 in head and neck squamous cell carcinoma.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/37160694","citation_count":2,"is_preprint":false},{"pmid":"38281249","id":"PMC_38281249","title":"Ribosomal protein S6 kinase 2 (RPS6KB2) is a potential immunotherapeutic target for cancer that upregulates proinflammatory cytokines.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38281249","citation_count":2,"is_preprint":false},{"pmid":"40886264","id":"PMC_40886264","title":"USF1-induced RPS6KB2 activation influences aggressive phenotype in B-cell non-Hodgkin lymphoma.","date":"2025","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/40886264","citation_count":2,"is_preprint":false},{"pmid":"28779262","id":"PMC_28779262","title":"Locus Mapping, Molecular Cloning, and Expression Analysis of rps6kb2, a Novel Metamorphosis-Related Gene in Chinese Tongue Sole (Cynoglossus semilaevis).","date":"2017","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28779262","citation_count":2,"is_preprint":false},{"pmid":"38602576","id":"PMC_38602576","title":"Knockdown siRNA Targeting GPR55 Reveals Significant Differences Between the Anti-inflammatory Actions of KLS-13019 and Cannabidiol.","date":"2024","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/38602576","citation_count":2,"is_preprint":false},{"pmid":"40126541","id":"PMC_40126541","title":"Nature-inspired designing of KLR- and KLS-rich antimicrobial peptides: unleashing the antibiofilm potential of RbP12 against MDR S. aureus and P. aeruginosa.","date":"2025","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/40126541","citation_count":2,"is_preprint":false},{"pmid":"37553546","id":"PMC_37553546","title":"Sleep Disorder Kleine-Levin Syndrome (KLS) Joins the List of Polygenic Brain Disorders Associated with Obstetric Complications.","date":"2023","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/37553546","citation_count":1,"is_preprint":false},{"pmid":"38464007","id":"PMC_38464007","title":"Knockdown siRNA targeting GPR55 reveals significant differences between the anti-inflammatory actions of KLS-13019 and cannabidiol.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38464007","citation_count":0,"is_preprint":false},{"pmid":"42005826","id":"PMC_42005826","title":"KLS-3021: Innovative oncolytic virotherapy for the treatment of advanced primary and metastatic cutaneous squamous cell carcinoma.","date":"2026","source":"Molecular therapy. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42005826","citation_count":0,"is_preprint":false},{"pmid":"41768263","id":"PMC_41768263","title":"KLS-3021, a multifunctional oncolytic virus, demonstrates potent early-intervention efficacy in preclinical models of prostate-confined and locally advanced prostate cancer.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41768263","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.13.682173","title":"The long non-coding RNA, CyKILRb, augments oncogenic phenotypes via induction of PIK3R2 and activation of the PI  <sub>3</sub>  K/AKT axis","date":"2025-10-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.13.682173","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11037,"output_tokens":1192,"usd":0.025496,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7806,"output_tokens":1747,"usd":0.041353,"stage2_stop_reason":"end_turn"},"total_usd":0.066849,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"USF1 transcription factor activates RPS6KB2 expression by directly binding to its promoter region; RPS6KB2 knockdown reduces cell proliferation, migration, and tumor growth while promoting apoptosis, and these effects are rescued by the AKT activator SC79, placing RPS6KB2 upstream of the AKT/HDM2/p53 signaling pathway in B-cell non-Hodgkin lymphoma.\",\n      \"method\": \"Bioinformatics promoter analysis, RT-qPCR, immunohistochemistry, western blot, siRNA knockdown, AKT activator rescue (SC79), functional proliferation/migration/apoptosis assays\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue and pathway placement by single lab using multiple orthogonal methods, but no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"40886264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPS6KB2 knockdown in hepatocellular carcinoma cells reduces cell proliferation, invasion, and migration, and upregulates proinflammatory cytokines (as measured by Bax, Bcl-2, MMP2, MMP9, PCNA expression changes), supporting a role for RPS6KB2 in cancer cell survival and immune modulation.\",\n      \"method\": \"siRNA knockdown, EDU cell proliferation assay, wound healing assay, Transwell invasion assay, western blot for apoptosis/migration markers and proinflammatory factors\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single KD approach with phenotypic readouts but limited pathway mechanistic detail\",\n      \"pmids\": [\"38281249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Chinese tongue sole (Cynoglossus semilaevis), rps6kb2 (an AGC kinase family member orthologous to mammalian RPS6KB2) maps to a metamorphosis-related quantitative trait locus; its expression peaks at metamorphic climax stage and is distributed in all tissues undergoing transformation (tail, jaw, eye, skin), suggesting a general role in tissue transformation during flatfish metamorphosis.\",\n      \"method\": \"Genetic linkage mapping, quantitative RT-PCR, whole-mount in situ hybridization\",\n      \"journal\": \"Marine biotechnology (New York, N.Y.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, expression-based localization in a fish ortholog, no direct functional manipulation of the protein\",\n      \"pmids\": [\"28779262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a lncRNA regulatory circuit, downregulation of CyKILRb causes loss of RPS6KB2 expression along with PIK3R2 and GNB2, while CyKILRb ectopic expression has the opposite effect, placing RPS6KB2 as a downstream effector of the CyKILRb→PIK3R2→PI3K→AKT axis in tumor promotion.\",\n      \"method\": \"Deep RNA sequencing, siRNA knockdown of CyKILRb, ectopic overexpression, PI3K/AKT inhibitor treatment, cell proliferation and clonogenic survival assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, RPS6KB2 is a downstream readout gene rather than the direct experimental target; no direct mechanistic manipulation of RPS6KB2 itself\",\n      \"pmids\": [\"bio_10.1101_2025.10.13.682173\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPS6KB2 (S6K2/p70S6Kβ) functions as a downstream effector of the AKT/mTORC1 signaling axis, where its transcription is activated by USF1 binding to its promoter, and its kinase activity promotes cell proliferation, survival, and migration through the AKT/HDM2/p53 pathway; its expression is also regulated downstream of a CyKILRb→PIK3R2→PI3K→AKT feed-forward circuit, and knockdown in cancer cells reduces proliferation and migration while enhancing proinflammatory cytokine secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPS6KB2 (S6K2) is a kinase that acts as a pro-tumorigenic effector within PI3K/AKT signaling, where its expression and activity promote cancer cell proliferation, migration, and survival [#0, #1]. In B-cell non-Hodgkin lymphoma, its transcription is directly activated by the transcription factor USF1 binding to its promoter, and its loss is rescued by AKT activation, placing RPS6KB2 upstream of the AKT/HDM2/p53 axis; knockdown reduces proliferation, migration, and tumor growth while promoting apoptosis [#0]. Consistent functional dependencies are observed in hepatocellular carcinoma, where knockdown suppresses proliferation, invasion, and migration and alters apoptotic (Bax/Bcl-2) and matrix-remodeling (MMP2/MMP9) markers while enhancing proinflammatory cytokine output [#1]. Beyond these phenotypic and transcriptional-regulatory observations, no direct biochemical characterization of RPS6KB2 substrates, catalytic mechanism, or structure is present in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that rps6kb2 expression correlates spatiotemporally with active tissue transformation, providing the first developmental-context association for the gene.\",\n      \"evidence\": \"Genetic linkage mapping, qRT-PCR, and in situ hybridization in a Chinese tongue sole ortholog\",\n      \"pmids\": [\"28779262\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression-only association in a fish ortholog with no functional manipulation\", \"No demonstration of a causal role in metamorphosis\", \"No connection to a defined signaling pathway\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that RPS6KB2 is functionally required for cancer cell proliferation, invasion, and migration, framing it as a survival/migration driver rather than a passive marker.\",\n      \"evidence\": \"siRNA knockdown with EdU, wound-healing, Transwell, and apoptosis/migration marker western blots in hepatocellular carcinoma cells\",\n      \"pmids\": [\"38281249\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown approach with phenotypic readouts only\", \"No direct mechanistic pathway linkage\", \"Marker changes do not establish direct substrates or upstream regulators\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined how RPS6KB2 is transcriptionally controlled and where it sits in oncogenic signaling, linking USF1-driven expression to the AKT/HDM2/p53 axis.\",\n      \"evidence\": \"Promoter analysis, RT-qPCR, IHC, siRNA knockdown, and AKT-activator (SC79) rescue with proliferation/migration/apoptosis assays in B-cell non-Hodgkin lymphoma\",\n      \"pmids\": [\"40886264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the USF1\\u2013promoter interaction beyond binding inference\", \"Connection to HDM2/p53 inferred from rescue rather than direct biochemistry\", \"Kinase substrates mediating the phenotype not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed RPS6KB2 as a downstream readout of a lncRNA-controlled PI3K/AKT feed-forward circuit, expanding its upstream regulatory context.\",\n      \"evidence\": \"RNA-seq, CyKILRb knockdown/overexpression, and PI3K/AKT inhibitor treatment with proliferation and clonogenic assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.13.682173\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"RPS6KB2 measured as a downstream readout without direct manipulation\", \"Mechanism linking CyKILRb/PIK3R2 to RPS6KB2 expression unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical activity of RPS6KB2 — its kinase substrates, catalytic regulation, and structural basis — remains uncharacterized in this corpus.\",\n      \"evidence\": \"No discovery directly assays RPS6KB2 enzymatic activity or substrate phosphorylation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No substrate identified\", \"No structural or biochemical kinase characterization\", \"Pathway placement rests on rescue/correlative rather than direct enzymatic evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}