{"gene":"RPL22L1","run_date":"2026-06-10T07:46:26","timeline":{"discoveries":[{"year":2013,"finding":"RPL22 directly represses RPL22L1 expression by binding to an internal hairpin structure in the RPL22L1 transcript, thereby controlling ribosome composition; in Rpl22-/- mice, compensatory upregulation of Rpl22l1 and its incorporation into ribosomes occurs, and knockdown of Rpl22l1 impairs growth of Rpl22-null cells.","method":"RNA binding assay (hairpin structure binding), genetic knockout mouse model (Rpl22-/-), ribosome fractionation, siRNA knockdown with growth assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assay, KO mouse, ribosome fractionation, siRNA rescue) in a single focused study with clear mechanistic readouts","pmids":["23990801"],"is_preprint":false},{"year":2017,"finding":"RPL22L1 (Like1) performs an extraribosomal function in the nucleus, where it promotes inclusion of exon 9 in smad2 pre-mRNA, antagonizing RPL22 which induces exon 9 skipping (in cooperation with hnRNP-A1); during gastrulation this antagonism controls morphogenesis through Nodal/TGF-β signaling.","method":"Subcellular fractionation/localization (nuclear localization), RNA immunoprecipitation (binding to intronic sequences of smad2 pre-mRNA), splicing reporter assays, genetic loss-of-function in zebrafish embryos","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, RIP, splicing assay, in vivo genetic model) in a single rigorous study","pmids":["28076796"],"is_preprint":false},{"year":2015,"finding":"RPL22L1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells, upregulating mesenchymal markers (vimentin, fibronectin, α-SMA) and reducing epithelial markers (E-cadherin, α-catenin, β-catenin); knockdown inhibits invasion and migration in vitro and in vivo.","method":"Overexpression and siRNA knockdown, invasion/migration assays, xenograft mouse model, Western blot for EMT markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional KD/OE with defined EMT phenotype, replicated in vivo, but no direct molecular target of RPL22L1 identified for EMT induction","pmids":["26618703"],"is_preprint":false},{"year":2022,"finding":"RPL22L1 activates the ERK signaling pathway to induce EMT and sorafenib resistance in hepatocellular carcinoma; ERK inhibition potentiates sorafenib efficacy in RPL22L1-high HCC cells.","method":"Overexpression and knockdown experiments, Western blot for ERK activation, drug sensitivity assays (sorafenib + ERK inhibitor combination), cell proliferation/migration/invasion assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single set of methods, pathway placement via inhibitor rescue but no direct binding of RPL22L1 to ERK pathway component demonstrated","pmids":["35973992"],"is_preprint":false},{"year":2023,"finding":"RPL22L1 promotes GBM malignancy and temozolomide resistance through activation of the EGFR/STAT3 pathway; STAT3 inhibitor (Stattic) suppresses RPL22L1-driven TMZ resistance both in vitro and in vivo.","method":"Overexpression and knockdown in GBM cells, orthotopic and subcutaneous xenograft models, Western blot for STAT3 pathway components, drug combination assays (Stattic + TMZ)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement via inhibitor rescue, no direct biochemical interaction between RPL22L1 and EGFR/STAT3 demonstrated","pmids":["37985768"],"is_preprint":false},{"year":2018,"finding":"miR-361-5p directly targets RPL22L1 (and c-Met), and reintroduction of RPL22L1 reverses miR-361-5p-induced EMT suppression in epithelial ovarian cancer cells, establishing RPL22L1 as a downstream effector of miR-361-5p in EMT regulation.","method":"Luciferase reporter assay (miR-361-5p targeting RPL22L1 3'UTR), overexpression rescue experiment, invasion/migration assays, Western blot for EMT markers","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — direct target validation by reporter assay and rescue, single lab, single study","pmids":["31938372"],"is_preprint":false},{"year":2025,"finding":"RPL22L1 competitively binds to the ERK phosphatase DUSP6, preventing ERK dephosphorylation and causing excessive ERK activation, thereby promoting malignant behavior and sorafenib resistance in cervical cancer.","method":"Co-immunoprecipitation (competitive binding assay between RPL22L1 and DUSP6), Western blot for ERK phosphorylation, overexpression/knockdown functional assays, in vivo xenograft, ERK inhibitor combination treatment","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — direct binding demonstrated by Co-IP, functional consequence validated by inhibitor rescue, single lab","pmids":["40022129"],"is_preprint":false},{"year":2025,"finding":"RPL22L1 activates the MAPK/ERK/Myc signaling pathway, inhibits Myc ubiquitination and degradation to stabilize Myc protein, and Myc in turn directly binds the RPL22L1 promoter (at -653 to -664) to enhance RPL22L1 transcription, forming a positive feedback loop that drives lung adenocarcinoma progression.","method":"Dual luciferase reporter assay (Myc binding to RPL22L1 promoter), ubiquitination immunoprecipitation assay, protein degradation assay, Western blot, overexpression/knockdown with proliferation/invasion assays, xenograft model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods (reporter assay, ubiquitination IP, protein stability assay) but single lab and no independent replication","pmids":["41044601"],"is_preprint":false},{"year":2024,"finding":"RPL22 deficiency promotes splicing of RPL22L1 pre-mRNA; RPL22 normally interacts with 28S rRNA and mRNA splice junctions and functions as a splicing regulator that suppresses RPL22L1 splicing, and this suppression is intensified by 28S rRNA sequestration.","method":"Multi-omics integration, genetic (RPL22 frameshift mutation analysis in cancer cell panel), RNA interaction studies (RPL22 binding to 28S rRNA and splice junctions), splicing analysis upon chemical/genetic inhibition of rRNA synthesis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mechanistic multi-omics study with genetic and chemical perturbations, but preprint and single lab","pmids":["bio_10.1101_2024.08.15.608201"],"is_preprint":true}],"current_model":"RPL22L1 is a ribosomal protein paralog of RPL22 whose expression is directly repressed by RPL22 binding to a hairpin in its transcript; RPL22L1 can substitute for RPL22 in ribosomes, and performs extraribosomal nuclear functions — most notably antagonizing RPL22 in regulating smad2 pre-mRNA splicing (promoting exon 9 inclusion) to control embryonic morphogenesis — while in cancer contexts it promotes EMT, drug resistance, and proliferation through mechanisms including competitive binding to the ERK phosphatase DUSP6 to hyperactivate ERK, activation of STAT3, and stabilization of Myc protein by inhibiting its ubiquitination."},"narrative":{"mechanistic_narrative":"RPL22L1 is a ribosomal protein paralog of RPL22 that doubles as a nuclear splicing regulator and, when overexpressed, as a driver of cancer malignancy [PMID:23990801, PMID:28076796]. Its expression is held in check by RPL22, which binds an internal hairpin in the RPL22L1 transcript and suppresses its splicing/expression, so that loss of RPL22 triggers compensatory RPL22L1 upregulation and incorporation into ribosomes to support cell growth [PMID:23990801, PMID:bio_10.1101_2024.08.15.608201]. Beyond ribosomes, RPL22L1 carries out an extraribosomal nuclear function by binding smad2 pre-mRNA and promoting inclusion of exon 9, directly antagonizing RPL22-driven exon skipping to tune Nodal/TGF-β signaling and morphogenesis during gastrulation [PMID:28076796]. In cancer, RPL22L1 promotes epithelial-to-mesenchymal transition, invasion, proliferation, and drug resistance across multiple tumor types [PMID:26618703, PMID:35973992]. Mechanistically it hyperactivates ERK signaling by competitively binding the ERK phosphatase DUSP6 to block ERK dephosphorylation [PMID:40022129], stabilizes Myc protein by inhibiting its ubiquitination within a Myc–RPL22L1 positive feedback loop [PMID:41044601], and engages EGFR/STAT3 signaling to drive temozolomide resistance [PMID:37985768]. RPL22L1 is itself a downstream effector of miR-361-5p, which represses it to suppress EMT [PMID:31938372].","teleology":[{"year":2013,"claim":"Established the regulatory relationship defining RPL22L1's place in ribosome biology: how a paralog's expression is controlled and whether it is functionally interchangeable with RPL22.","evidence":"RNA hairpin binding assay, Rpl22-/- mouse, ribosome fractionation and siRNA rescue","pmids":["23990801"],"confidence":"High","gaps":["Does not define whether RPL22L1-containing ribosomes translate a distinct mRNA subset","Mechanism of hairpin recognition not structurally resolved"]},{"year":2017,"claim":"Revealed that RPL22L1 has an extraribosomal nuclear role, acting as a splicing regulator that antagonizes RPL22 rather than merely substituting for it in ribosomes.","evidence":"Nuclear fractionation, RIP on smad2 intronic sequences, splicing reporters, zebrafish loss-of-function","pmids":["28076796"],"confidence":"High","gaps":["Direct RNA-binding determinants of RPL22L1 not mapped","Whether the splicing role extends beyond smad2 unknown","Cofactor requirements (cf. RPL22/hnRNP-A1) not defined for RPL22L1"]},{"year":2015,"claim":"Connected RPL22L1 to a cancer phenotype by showing overexpression drives EMT and metastatic behavior, framing it as an oncogenic effector.","evidence":"Overexpression/knockdown, invasion/migration assays, xenograft, EMT-marker Western blots in ovarian cancer","pmids":["26618703"],"confidence":"Medium","gaps":["No direct molecular target linking RPL22L1 to EMT identified in this study","Does not distinguish ribosomal versus extraribosomal contribution"]},{"year":2018,"claim":"Placed RPL22L1 within an upstream regulatory circuit by identifying it as a direct miR-361-5p target whose re-expression rescues EMT suppression.","evidence":"Luciferase 3'UTR reporter, overexpression rescue, invasion/migration and EMT-marker assays in ovarian cancer","pmids":["31938372"],"confidence":"Medium","gaps":["Single study, single lab","Downstream effectors of RPL22L1 in this axis not resolved"]},{"year":2022,"claim":"Began assigning a signaling pathway to RPL22L1's oncogenic action by linking it to ERK activation and sorafenib resistance.","evidence":"Overexpression/knockdown, ERK Western blots, sorafenib + ERK inhibitor drug assays in HCC","pmids":["35973992"],"confidence":"Medium","gaps":["No direct binding to an ERK-pathway component shown here","Pathway placement inferred from inhibitor rescue only"]},{"year":2023,"claim":"Extended the pathway repertoire by implicating EGFR/STAT3 signaling in RPL22L1-driven malignancy and temozolomide resistance.","evidence":"Overexpression/knockdown in GBM, orthotopic/subcutaneous xenografts, STAT3 Western blots, Stattic + TMZ combination","pmids":["37985768"],"confidence":"Medium","gaps":["No direct biochemical interaction between RPL22L1 and EGFR/STAT3 demonstrated","Single lab"]},{"year":2024,"claim":"Refined the RPL22-RPL22L1 control mechanism by showing RPL22 suppresses RPL22L1 at the splicing level and that 28S rRNA sequestration of RPL22 intensifies this repression.","evidence":"Multi-omics, RPL22 frameshift analysis in cancer cell panel, RPL22–28S rRNA/splice-junction interaction studies, rRNA-synthesis perturbation (preprint)","pmids":["bio_10.1101_2024.08.15.608201"],"confidence":"Medium","gaps":["Preprint, single lab","Quantitative contribution of rRNA sequestration versus direct transcript binding unresolved"]},{"year":2025,"claim":"Provided the first direct molecular mechanism for RPL22L1-driven ERK hyperactivation: competitive binding to the phosphatase DUSP6 that blocks ERK dephosphorylation.","evidence":"Co-IP competitive binding with DUSP6, ERK-phosphorylation Western blots, functional assays, xenograft, ERK inhibitor combination in cervical cancer","pmids":["40022129"],"confidence":"Medium","gaps":["Single lab, no reciprocal/structural validation of the RPL22L1-DUSP6 interface","Whether DUSP6 binding accounts for ERK effects in other tumor types not tested"]},{"year":2025,"claim":"Identified a Myc-stabilizing mechanism and a self-reinforcing loop, showing RPL22L1 inhibits Myc ubiquitination while Myc transcriptionally activates RPL22L1.","evidence":"Promoter luciferase reporter, ubiquitination IP, protein-stability assays, functional assays and xenograft in lung adenocarcinoma","pmids":["41044601"],"confidence":"Medium","gaps":["Direct versus indirect inhibition of Myc ubiquitination not distinguished","Single lab, no independent replication"]},{"year":null,"claim":"It remains unresolved how RPL22L1's ribosomal, nuclear splicing, and cytoplasmic signaling activities are mechanistically partitioned and whether they share a common biochemical basis.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of RPL22L1 or its RNA/protein-binding interfaces","Whether splicing regulation contributes to its oncogenic phenotypes is untested","Direct interactors driving STAT3 and EMT phenotypes not biochemically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,4]}],"complexes":["ribosome"],"partners":["RPL22","DUSP6","SMAD2","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P5R6","full_name":"Ribosomal protein eL22-like","aliases":["60S ribosomal protein L22-like 1","Large ribosomal subunit protein eL22-like 1"],"length_aa":122,"mass_kda":14.6,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6P5R6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL22L1","classification":"Not Classified","n_dependent_lines":148,"n_total_lines":1208,"dependency_fraction":0.12251655629139073},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM3","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RPL22L1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli rim","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL22L1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6P5R6","domains":[{"cath_id":"3.30.1360.210","chopping":"13-107","consensus_level":"high","plddt":95.5359,"start":13,"end":107}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P5R6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P5R6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P5R6-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL22L1","jax_strain_url":"https://www.jax.org/strain/search?query=RPL22L1"},"sequence":{"accession":"Q6P5R6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P5R6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P5R6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P5R6"}},"corpus_meta":[{"pmid":"23990801","id":"PMC_23990801","title":"The ribosomal protein Rpl22 controls ribosome composition by directly repressing expression of its own paralog, Rpl22l1.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23990801","citation_count":107,"is_preprint":false},{"pmid":"28076796","id":"PMC_28076796","title":"Ribosomal Proteins Rpl22 and Rpl22l1 Control Morphogenesis by Regulating Pre-mRNA Splicing.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28076796","citation_count":81,"is_preprint":false},{"pmid":"26618703","id":"PMC_26618703","title":"Ribosomal L22-like1 (RPL22L1) Promotes Ovarian Cancer Metastasis by Inducing Epithelial-to-Mesenchymal Transition.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26618703","citation_count":34,"is_preprint":false},{"pmid":"35973992","id":"PMC_35973992","title":"Ribosomal protein L22-like1 (RPL22L1) mediates sorafenib sensitivity via ERK in hepatocellular carcinoma.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35973992","citation_count":17,"is_preprint":false},{"pmid":"37985768","id":"PMC_37985768","title":"RPL22L1, a novel candidate oncogene promotes temozolomide resistance by activating STAT3 in glioblastoma.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37985768","citation_count":14,"is_preprint":false},{"pmid":"31938372","id":"PMC_31938372","title":"MiR-361-5p decreases the tumorigenicity of epithelial ovarian cancer cells by targeting at RPL22L1 and c-Met signaling.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31938372","citation_count":9,"is_preprint":false},{"pmid":"40022129","id":"PMC_40022129","title":"RPL22L1 fosters malignant features of cervical cancer via the modulation of DUSP6-ERK axis.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40022129","citation_count":3,"is_preprint":false},{"pmid":"39079325","id":"PMC_39079325","title":"Arsenic trioxide regulates the glycolytic pathway to treat acute promyelocytic leukemia by inhibiting RPL22L1.","date":"2024","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/39079325","citation_count":1,"is_preprint":false},{"pmid":"41044601","id":"PMC_41044601","title":"RPL22L1-Myc positive feedback loop drives lung adenocarcinoma progression.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41044601","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.13.681987","title":"Distinct 5′ and 3′ Coverage Biases Shape Transcriptome Interpretation in Nanopore Direct RNA versus PCR-cDNA Sequencing","date":"2025-10-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.13.681987","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.10.663151","title":"Early-life stress as a potential resilience factor in king penguins","date":"2025-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.10.663151","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.15.608201","title":"Ribosomal RNA transcription governs splicing through ribosomal protein RPL22","date":"2024-08-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.15.608201","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7993,"output_tokens":2384,"usd":0.02987,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9539,"output_tokens":3184,"usd":0.063647,"stage2_stop_reason":"end_turn"},"total_usd":0.093517,"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\": 2013,\n      \"finding\": \"RPL22 directly represses RPL22L1 expression by binding to an internal hairpin structure in the RPL22L1 transcript, thereby controlling ribosome composition; in Rpl22-/- mice, compensatory upregulation of Rpl22l1 and its incorporation into ribosomes occurs, and knockdown of Rpl22l1 impairs growth of Rpl22-null cells.\",\n      \"method\": \"RNA binding assay (hairpin structure binding), genetic knockout mouse model (Rpl22-/-), ribosome fractionation, siRNA knockdown with growth assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assay, KO mouse, ribosome fractionation, siRNA rescue) in a single focused study with clear mechanistic readouts\",\n      \"pmids\": [\"23990801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RPL22L1 (Like1) performs an extraribosomal function in the nucleus, where it promotes inclusion of exon 9 in smad2 pre-mRNA, antagonizing RPL22 which induces exon 9 skipping (in cooperation with hnRNP-A1); during gastrulation this antagonism controls morphogenesis through Nodal/TGF-β signaling.\",\n      \"method\": \"Subcellular fractionation/localization (nuclear localization), RNA immunoprecipitation (binding to intronic sequences of smad2 pre-mRNA), splicing reporter assays, genetic loss-of-function in zebrafish embryos\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, RIP, splicing assay, in vivo genetic model) in a single rigorous study\",\n      \"pmids\": [\"28076796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPL22L1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells, upregulating mesenchymal markers (vimentin, fibronectin, α-SMA) and reducing epithelial markers (E-cadherin, α-catenin, β-catenin); knockdown inhibits invasion and migration in vitro and in vivo.\",\n      \"method\": \"Overexpression and siRNA knockdown, invasion/migration assays, xenograft mouse model, Western blot for EMT markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional KD/OE with defined EMT phenotype, replicated in vivo, but no direct molecular target of RPL22L1 identified for EMT induction\",\n      \"pmids\": [\"26618703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RPL22L1 activates the ERK signaling pathway to induce EMT and sorafenib resistance in hepatocellular carcinoma; ERK inhibition potentiates sorafenib efficacy in RPL22L1-high HCC cells.\",\n      \"method\": \"Overexpression and knockdown experiments, Western blot for ERK activation, drug sensitivity assays (sorafenib + ERK inhibitor combination), cell proliferation/migration/invasion assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of methods, pathway placement via inhibitor rescue but no direct binding of RPL22L1 to ERK pathway component demonstrated\",\n      \"pmids\": [\"35973992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RPL22L1 promotes GBM malignancy and temozolomide resistance through activation of the EGFR/STAT3 pathway; STAT3 inhibitor (Stattic) suppresses RPL22L1-driven TMZ resistance both in vitro and in vivo.\",\n      \"method\": \"Overexpression and knockdown in GBM cells, orthotopic and subcutaneous xenograft models, Western blot for STAT3 pathway components, drug combination assays (Stattic + TMZ)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement via inhibitor rescue, no direct biochemical interaction between RPL22L1 and EGFR/STAT3 demonstrated\",\n      \"pmids\": [\"37985768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-361-5p directly targets RPL22L1 (and c-Met), and reintroduction of RPL22L1 reverses miR-361-5p-induced EMT suppression in epithelial ovarian cancer cells, establishing RPL22L1 as a downstream effector of miR-361-5p in EMT regulation.\",\n      \"method\": \"Luciferase reporter assay (miR-361-5p targeting RPL22L1 3'UTR), overexpression rescue experiment, invasion/migration assays, Western blot for EMT markers\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct target validation by reporter assay and rescue, single lab, single study\",\n      \"pmids\": [\"31938372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPL22L1 competitively binds to the ERK phosphatase DUSP6, preventing ERK dephosphorylation and causing excessive ERK activation, thereby promoting malignant behavior and sorafenib resistance in cervical cancer.\",\n      \"method\": \"Co-immunoprecipitation (competitive binding assay between RPL22L1 and DUSP6), Western blot for ERK phosphorylation, overexpression/knockdown functional assays, in vivo xenograft, ERK inhibitor combination treatment\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct binding demonstrated by Co-IP, functional consequence validated by inhibitor rescue, single lab\",\n      \"pmids\": [\"40022129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPL22L1 activates the MAPK/ERK/Myc signaling pathway, inhibits Myc ubiquitination and degradation to stabilize Myc protein, and Myc in turn directly binds the RPL22L1 promoter (at -653 to -664) to enhance RPL22L1 transcription, forming a positive feedback loop that drives lung adenocarcinoma progression.\",\n      \"method\": \"Dual luciferase reporter assay (Myc binding to RPL22L1 promoter), ubiquitination immunoprecipitation assay, protein degradation assay, Western blot, overexpression/knockdown with proliferation/invasion assays, xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods (reporter assay, ubiquitination IP, protein stability assay) but single lab and no independent replication\",\n      \"pmids\": [\"41044601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPL22 deficiency promotes splicing of RPL22L1 pre-mRNA; RPL22 normally interacts with 28S rRNA and mRNA splice junctions and functions as a splicing regulator that suppresses RPL22L1 splicing, and this suppression is intensified by 28S rRNA sequestration.\",\n      \"method\": \"Multi-omics integration, genetic (RPL22 frameshift mutation analysis in cancer cell panel), RNA interaction studies (RPL22 binding to 28S rRNA and splice junctions), splicing analysis upon chemical/genetic inhibition of rRNA synthesis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic multi-omics study with genetic and chemical perturbations, but preprint and single lab\",\n      \"pmids\": [\"bio_10.1101_2024.08.15.608201\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPL22L1 is a ribosomal protein paralog of RPL22 whose expression is directly repressed by RPL22 binding to a hairpin in its transcript; RPL22L1 can substitute for RPL22 in ribosomes, and performs extraribosomal nuclear functions — most notably antagonizing RPL22 in regulating smad2 pre-mRNA splicing (promoting exon 9 inclusion) to control embryonic morphogenesis — while in cancer contexts it promotes EMT, drug resistance, and proliferation through mechanisms including competitive binding to the ERK phosphatase DUSP6 to hyperactivate ERK, activation of STAT3, and stabilization of Myc protein by inhibiting its ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL22L1 is a ribosomal protein paralog of RPL22 that doubles as a nuclear splicing regulator and, when overexpressed, as a driver of cancer malignancy [#0, #1]. Its expression is held in check by RPL22, which binds an internal hairpin in the RPL22L1 transcript and suppresses its splicing/expression, so that loss of RPL22 triggers compensatory RPL22L1 upregulation and incorporation into ribosomes to support cell growth [#0, #8]. Beyond ribosomes, RPL22L1 carries out an extraribosomal nuclear function by binding smad2 pre-mRNA and promoting inclusion of exon 9, directly antagonizing RPL22-driven exon skipping to tune Nodal/TGF-\\u03b2 signaling and morphogenesis during gastrulation [#1]. In cancer, RPL22L1 promotes epithelial-to-mesenchymal transition, invasion, proliferation, and drug resistance across multiple tumor types [#2, #3]. Mechanistically it hyperactivates ERK signaling by competitively binding the ERK phosphatase DUSP6 to block ERK dephosphorylation [#6], stabilizes Myc protein by inhibiting its ubiquitination within a Myc\\u2013RPL22L1 positive feedback loop [#7], and engages EGFR/STAT3 signaling to drive temozolomide resistance [#4]. RPL22L1 is itself a downstream effector of miR-361-5p, which represses it to suppress EMT [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the regulatory relationship defining RPL22L1's place in ribosome biology: how a paralog's expression is controlled and whether it is functionally interchangeable with RPL22.\",\n      \"evidence\": \"RNA hairpin binding assay, Rpl22-/- mouse, ribosome fractionation and siRNA rescue\",\n      \"pmids\": [\"23990801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define whether RPL22L1-containing ribosomes translate a distinct mRNA subset\", \"Mechanism of hairpin recognition not structurally resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed that RPL22L1 has an extraribosomal nuclear role, acting as a splicing regulator that antagonizes RPL22 rather than merely substituting for it in ribosomes.\",\n      \"evidence\": \"Nuclear fractionation, RIP on smad2 intronic sequences, splicing reporters, zebrafish loss-of-function\",\n      \"pmids\": [\"28076796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding determinants of RPL22L1 not mapped\", \"Whether the splicing role extends beyond smad2 unknown\", \"Cofactor requirements (cf. RPL22/hnRNP-A1) not defined for RPL22L1\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected RPL22L1 to a cancer phenotype by showing overexpression drives EMT and metastatic behavior, framing it as an oncogenic effector.\",\n      \"evidence\": \"Overexpression/knockdown, invasion/migration assays, xenograft, EMT-marker Western blots in ovarian cancer\",\n      \"pmids\": [\"26618703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular target linking RPL22L1 to EMT identified in this study\", \"Does not distinguish ribosomal versus extraribosomal contribution\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed RPL22L1 within an upstream regulatory circuit by identifying it as a direct miR-361-5p target whose re-expression rescues EMT suppression.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, overexpression rescue, invasion/migration and EMT-marker assays in ovarian cancer\",\n      \"pmids\": [\"31938372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"Downstream effectors of RPL22L1 in this axis not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Began assigning a signaling pathway to RPL22L1's oncogenic action by linking it to ERK activation and sorafenib resistance.\",\n      \"evidence\": \"Overexpression/knockdown, ERK Western blots, sorafenib + ERK inhibitor drug assays in HCC\",\n      \"pmids\": [\"35973992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding to an ERK-pathway component shown here\", \"Pathway placement inferred from inhibitor rescue only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the pathway repertoire by implicating EGFR/STAT3 signaling in RPL22L1-driven malignancy and temozolomide resistance.\",\n      \"evidence\": \"Overexpression/knockdown in GBM, orthotopic/subcutaneous xenografts, STAT3 Western blots, Stattic + TMZ combination\",\n      \"pmids\": [\"37985768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction between RPL22L1 and EGFR/STAT3 demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the RPL22-RPL22L1 control mechanism by showing RPL22 suppresses RPL22L1 at the splicing level and that 28S rRNA sequestration of RPL22 intensifies this repression.\",\n      \"evidence\": \"Multi-omics, RPL22 frameshift analysis in cancer cell panel, RPL22\\u201328S rRNA/splice-junction interaction studies, rRNA-synthesis perturbation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.08.15.608201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Quantitative contribution of rRNA sequestration versus direct transcript binding unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the first direct molecular mechanism for RPL22L1-driven ERK hyperactivation: competitive binding to the phosphatase DUSP6 that blocks ERK dephosphorylation.\",\n      \"evidence\": \"Co-IP competitive binding with DUSP6, ERK-phosphorylation Western blots, functional assays, xenograft, ERK inhibitor combination in cervical cancer\",\n      \"pmids\": [\"40022129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no reciprocal/structural validation of the RPL22L1-DUSP6 interface\", \"Whether DUSP6 binding accounts for ERK effects in other tumor types not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a Myc-stabilizing mechanism and a self-reinforcing loop, showing RPL22L1 inhibits Myc ubiquitination while Myc transcriptionally activates RPL22L1.\",\n      \"evidence\": \"Promoter luciferase reporter, ubiquitination IP, protein-stability assays, functional assays and xenograft in lung adenocarcinoma\",\n      \"pmids\": [\"41044601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect inhibition of Myc ubiquitination not distinguished\", \"Single lab, no independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RPL22L1's ribosomal, nuclear splicing, and cytoplasmic signaling activities are mechanistically partitioned and whether they share a common biochemical basis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of RPL22L1 or its RNA/protein-binding interfaces\", \"Whether splicing regulation contributes to its oncogenic phenotypes is untested\", \"Direct interactors driving STAT3 and EMT phenotypes not biochemically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 4]}\n    ],\n    \"complexes\": [\"ribosome\"],\n    \"partners\": [\"RPL22\", \"DUSP6\", \"SMAD2\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}