{"gene":"CCDC137","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2023,"finding":"CCDC137 functions as an RNA-binding protein that binds FOXM1, JTV1, LASP1, and FLOT2 mRNAs (identified by APOBEC1-mediated profiling), increasing their cytoplasmic localization and enhancing their protein expression, which synergistically activates AKT signaling to promote hepatocellular carcinoma progression.","method":"APOBEC1-mediated RNA profiling, in vitro cell assays, in vivo mouse models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — APOBEC1-mediated profiling combined with functional cell and animal assays, single lab, multiple orthogonal methods","pmids":["37542342"],"is_preprint":false},{"year":2023,"finding":"CCDC137 binds the microprocessor protein DGCR8, and this interaction mediates cytoplasmic distribution of mRNAs regulated by CCDC137, revealing a novel non-canonical role for DGCR8 in mRNA subcellular localization.","method":"Co-immunoprecipitation, functional localization assays, in vitro and in vivo experiments","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional mRNA localization assays, single lab, multiple methods","pmids":["37542342"],"is_preprint":false},{"year":2024,"finding":"CCDC137 binds LZTS2 (a negative regulator of β-catenin) and recruits E3 ubiquitin ligase β-TrCP in the nucleus to facilitate K48-linked poly-ubiquitination of LZTS2 at lysine 467, thereby triggering AKT phosphorylation and activation of the β-catenin pathway to promote HCC progression. The 1–75 domain of CCDC137 is responsible for the CCDC137-LZTS2-β-TrCP complex formation.","method":"Co-immunoprecipitation, ubiquitination assays, domain mapping, peptide disruption in HCC organoids and PDX models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, site-specific ubiquitination mapping, domain deletion, multiple model systems (organoids, PDX), single lab but multiple orthogonal methods","pmids":["38918619"],"is_preprint":false},{"year":2025,"finding":"HIV Vpr causes ATR-dependent nucleolar stress that leads to degradation of the nucleolar protein CCDC137. CCDC137 degradation is conserved among pandemic HIV-1 and related SIVcpz/SIVgor Vpr variants, is triggered by genomic insults that activate a nucleolar ATR pathway (similar to camptothecin), and correlates with redistribution of nucleolar proteins, altered nucleolar morphology, and repressed ribosome biogenesis. CCDC137 degradation does not correlate with Vpr-induced G2/M arrest.","method":"Vpr functional genetics, ATR pathway inhibition, nucleolar protein localization assays, ribosome biogenesis assays, comparison across Vpr variants","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetics, inhibition, localization, biogenesis assays), single lab","pmids":["40530693"],"is_preprint":false},{"year":2025,"finding":"CCDC137 knockdown in bladder cancer cells results in decreased expression of stearoyl-CoA desaturase (SCD), a key lipid metabolic enzyme, suggesting CCDC137 regulates lipid metabolism via SCD to promote bladder cancer progression.","method":"RNA sequencing, RT-PCR, western blot, CCK8, clonogenic, wound healing, Transwell assays, subcutaneous xenograft models","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, downstream correlation between CCDC137 KD and SCD levels without direct mechanistic link established","pmids":["40993629"],"is_preprint":false},{"year":2025,"finding":"CCDC137 interacts with DGCR8 and promotes aerobic glycolysis in hepatocellular carcinoma through activation of the AKT/mTOR signaling pathway.","method":"Bioinformatics, functional cell assays, western blot, Co-IP (implied by interaction claim)","journal":"European journal of medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanism described as potential/may-be with limited direct mechanistic validation reported in abstract","pmids":["41029756"],"is_preprint":false},{"year":2026,"finding":"CCDC137 interacts with S100A6 protein via co-immunoprecipitation, significantly enhancing S100A6 protein stability. Stabilized S100A6 in turn activates the PI3K/AKT signaling pathway, driving acute myeloid leukemia cell proliferation and cell cycle progression.","method":"Co-immunoprecipitation (Co-IP), protein stability assays, functional proliferation and cell cycle experiments","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with protein stability functional follow-up, single lab, two orthogonal methods","pmids":["41964482"],"is_preprint":false},{"year":2026,"finding":"CCDC137 activates the AKT/mTOR signaling pathway in sorafenib-resistant HCC cells; CCDC137 knockdown suppresses this pathway, while overexpression enhances sorafenib resistance. AKT inhibition with MK2206 reverses CCDC137-driven resistance.","method":"Western blot, knockdown/overexpression experiments, pharmacological AKT inhibition, in vitro cell viability and apoptosis assays","journal":"Clinical & translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway activation confirmed by western blot but upstream mechanism linking CCDC137 to AKT not directly established","pmids":["41632344"],"is_preprint":false},{"year":2022,"finding":"CDK12 orchestrates transcription of SE-associated CCDC137 as an oncogenic gene in colorectal cancer; CDK12 inhibition preferentially represses CCDC137 transcription, reducing cellular survival, proliferation, and stemness, and ultimately liver metastasis.","method":"shRNA knockdown, selective CDK12 inhibitor (SR-4835), RNA sequencing, super-enhancer landscape integration, in vitro and in vivo assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq integrated with SE landscape, functional in vitro and in vivo validation, single lab","pmids":["36254394"],"is_preprint":false}],"current_model":"CCDC137 is a nucleolar RNA-binding protein that, in cancer contexts, binds specific mRNAs (FOXM1, JTV1, LASP1, FLOT2) to promote their cytoplasmic localization via interaction with DGCR8, forms a nuclear complex with LZTS2 and β-TrCP to drive K48-linked ubiquitination of LZTS2 at K467 activating β-catenin and AKT, stabilizes S100A6 to engage PI3K/AKT, and in normal biology serves as a sensor of nucleolar stress whose degradation is triggered by an ATR-dependent pathway in response to DNA damage."},"narrative":{"mechanistic_narrative":"CCDC137 is a nucleolar protein that has emerged primarily as an oncogenic effector across multiple cancers, where it converges on AKT-axis signaling to drive proliferation and disease progression [PMID:37542342, PMID:38918619]. As an RNA-binding protein, it binds a defined set of mRNAs (FOXM1, JTV1, LASP1, FLOT2) and, through interaction with the microprocessor protein DGCR8, promotes their cytoplasmic localization and elevated protein output, thereby activating AKT signaling in hepatocellular carcinoma [PMID:37542342]. In a distinct nuclear function, CCDC137 binds the β-catenin negative regulator LZTS2 and recruits the E3 ligase β-TrCP to catalyze K48-linked polyubiquitination of LZTS2 at lysine 467 via its 1–75 domain, triggering AKT phosphorylation and β-catenin pathway activation [PMID:38918619]. It also acts as a protein stabilizer, binding S100A6 to enhance its stability and engage PI3K/AKT signaling in acute myeloid leukemia [PMID:41964482]. In normal biology, CCDC137 behaves as a nucleolar stress sensor: HIV Vpr and genotoxic insults activate an ATR-dependent nucleolar pathway that drives its degradation, accompanied by nucleolar protein redistribution and repressed ribosome biogenesis [PMID:40530693]. Its transcription is itself driven by CDK12 through super-enhancer regulation in colorectal cancer [PMID:36254394].","teleology":[{"year":2022,"claim":"Established how CCDC137 expression is controlled, identifying it as a super-enhancer-associated oncogenic target of CDK12 transcriptional regulation.","evidence":"shRNA knockdown, selective CDK12 inhibitor (SR-4835), RNA-seq integrated with super-enhancer landscape, and in vivo metastasis assays in colorectal cancer","pmids":["36254394"],"confidence":"Medium","gaps":["Does not address the molecular function of the CCDC137 protein itself","Mechanism by which CCDC137 supports survival/stemness downstream not defined here"]},{"year":2023,"claim":"Defined CCDC137 as an RNA-binding protein that uses DGCR8 to redirect specific mRNAs to the cytoplasm, providing a mechanistic basis for its activation of AKT signaling.","evidence":"APOBEC1-mediated RNA profiling, Co-IP with DGCR8, mRNA localization assays, and in vitro/in vivo HCC models","pmids":["37542342"],"confidence":"Medium","gaps":["Direct RNA-binding domain of CCDC137 not mapped","How DGCR8 is repurposed from microprocessor to mRNA-localization role mechanistically unresolved","Single lab"]},{"year":2024,"claim":"Revealed a separate nuclear scaffolding function in which CCDC137 directs ubiquitin-mediated degradation of a β-catenin antagonist, linking it to β-catenin/AKT activation.","evidence":"Reciprocal Co-IP, site-specific (K467) ubiquitination mapping, domain deletion (1–75), and peptide disruption in HCC organoids and PDX models","pmids":["38918619"],"confidence":"High","gaps":["How CCDC137 selects LZTS2 as substrate-presenting partner not defined","Relationship between this nuclear function and the RNA-binding function unclear"]},{"year":2025,"claim":"Identified CCDC137 as a target of nucleolar stress in normal biology, degraded through an ATR-dependent pathway upon HIV Vpr expression or genotoxic insult.","evidence":"Vpr functional genetics, ATR pathway inhibition, nucleolar localization and ribosome biogenesis assays, comparison across Vpr variants","pmids":["40530693"],"confidence":"Medium","gaps":["The E3 ligase mediating CCDC137 degradation not identified","Whether CCDC137 loss is cause or consequence of nucleolar disruption not resolved","Degradation uncoupled from G2/M arrest but functional consequence of loss unclear"]},{"year":2026,"claim":"Extended the protein-stabilizing mode of CCDC137 to S100A6, connecting it to PI3K/AKT-driven proliferation in acute myeloid leukemia.","evidence":"Co-IP, protein stability assays, and proliferation/cell-cycle functional experiments","pmids":["41964482"],"confidence":"Medium","gaps":["Mechanism of S100A6 stabilization (e.g. blocking degradation) not detailed","Whether interaction is direct not established"]},{"year":null,"claim":"It remains unknown how CCDC137's nucleolar localization and stress-sensor role mechanistically relate to its cytoplasmic oncogenic functions, and whether a single biochemical activity underlies its RNA-binding, ubiquitin-scaffolding, and protein-stabilizing roles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CCDC137 or its functional domains beyond the 1–75 region","No unifying biochemical activity defined across reported functions","Lipid-metabolism (SCD) and AKT/mTOR roles rest on correlative single-lab data"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"complexes":[],"partners":["DGCR8","LZTS2","BTRC","S100A6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PK04","full_name":"Coiled-coil domain-containing protein 137","aliases":[],"length_aa":289,"mass_kda":33.2,"function":"","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q6PK04/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC137","classification":"Common Essential","n_dependent_lines":500,"n_total_lines":1208,"dependency_fraction":0.4139072847682119},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NPM1","stoichiometry":0.2},{"gene":"PTMA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCDC137","total_profiled":1310},"omim":[{"mim_id":"614271","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 137; CCDC137","url":"https://www.omim.org/entry/614271"},{"mim_id":"181500","title":"SCHIZOPHRENIA; SCZD","url":"https://www.omim.org/entry/181500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC137"},"hgnc":{"alias_symbol":["MGC16597"],"prev_symbol":[]},"alphafold":{"accession":"Q6PK04","domains":[{"cath_id":"-","chopping":"66-142","consensus_level":"medium","plddt":83.9151,"start":66,"end":142}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PK04","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PK04-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PK04-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC137","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC137"},"sequence":{"accession":"Q6PK04","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PK04.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PK04/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PK04"}},"corpus_meta":[{"pmid":"36254394","id":"PMC_36254394","title":"CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36254394","citation_count":23,"is_preprint":false},{"pmid":"37542342","id":"PMC_37542342","title":"RNA-binding protein CCDC137 activates AKT signaling and promotes hepatocellular carcinoma through a novel non-canonical role of DGCR8 in mRNA localization.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37542342","citation_count":18,"is_preprint":false},{"pmid":"38918619","id":"PMC_38918619","title":"Disrupting CCDC137-mediated LZTS2 and β-TrCP interaction in the nucleus inhibits hepatocellular carcinoma development via β-catenin and AKT.","date":"2024","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/38918619","citation_count":10,"is_preprint":false},{"pmid":"40993629","id":"PMC_40993629","title":"CCDC137 knockdown suppresses bladder cancer progression by downregulating SCD.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40993629","citation_count":3,"is_preprint":false},{"pmid":"38174951","id":"PMC_38174951","title":"Integrated RNA expression and alternative polyadenylation analysis identified CPSF1-CCDC137 oncogenic axis in lung adenocarcinoma.","date":"2024","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38174951","citation_count":3,"is_preprint":false},{"pmid":"40530693","id":"PMC_40530693","title":"HIV Vpr activates a nucleolar-specific ATR pathway to degrade the nucleolar stress sensor CCDC137.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40530693","citation_count":0,"is_preprint":false},{"pmid":"41416436","id":"PMC_41416436","title":"CCDC137: A key hub for RNA and epigenetic regulation in cancer research (Review).","date":"2025","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41416436","citation_count":0,"is_preprint":false},{"pmid":"41029756","id":"PMC_41029756","title":"CCDC137/DGCR8 axis promotes aerobic glycolysis in hepatocellular carcinoma via activation of the AKT/mTOR signaling pathway.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41029756","citation_count":0,"is_preprint":false},{"pmid":"41964482","id":"PMC_41964482","title":"CCDC137 stabilizes S100A6 to activate the PI3K/AKT pathway and drive acute myeloid leukemia progression.","date":"2026","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/41964482","citation_count":0,"is_preprint":false},{"pmid":"39838867","id":"PMC_39838867","title":"RETRACTION: Integrated RNA Expression and Alternative Polyadenylation Analysis Identified CPSF1-CCDC137 Oncogenic Axis in Lung Adenocarcinoma.","date":"2025","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39838867","citation_count":0,"is_preprint":false},{"pmid":"41632344","id":"PMC_41632344","title":"CCDC137 affects sorafenib resistance in hepatocellular carcinoma cells by activating the AKT/mTOR signaling pathway.","date":"2026","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/41632344","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7490,"output_tokens":2195,"usd":0.027697,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9279,"output_tokens":2327,"usd":0.052285,"stage2_stop_reason":"end_turn"},"total_usd":0.079982,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC137 functions as an RNA-binding protein that binds FOXM1, JTV1, LASP1, and FLOT2 mRNAs (identified by APOBEC1-mediated profiling), increasing their cytoplasmic localization and enhancing their protein expression, which synergistically activates AKT signaling to promote hepatocellular carcinoma progression.\",\n      \"method\": \"APOBEC1-mediated RNA profiling, in vitro cell assays, in vivo mouse models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — APOBEC1-mediated profiling combined with functional cell and animal assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37542342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC137 binds the microprocessor protein DGCR8, and this interaction mediates cytoplasmic distribution of mRNAs regulated by CCDC137, revealing a novel non-canonical role for DGCR8 in mRNA subcellular localization.\",\n      \"method\": \"Co-immunoprecipitation, functional localization assays, in vitro and in vivo experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional mRNA localization assays, single lab, multiple methods\",\n      \"pmids\": [\"37542342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC137 binds LZTS2 (a negative regulator of β-catenin) and recruits E3 ubiquitin ligase β-TrCP in the nucleus to facilitate K48-linked poly-ubiquitination of LZTS2 at lysine 467, thereby triggering AKT phosphorylation and activation of the β-catenin pathway to promote HCC progression. The 1–75 domain of CCDC137 is responsible for the CCDC137-LZTS2-β-TrCP complex formation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, domain mapping, peptide disruption in HCC organoids and PDX models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, site-specific ubiquitination mapping, domain deletion, multiple model systems (organoids, PDX), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38918619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIV Vpr causes ATR-dependent nucleolar stress that leads to degradation of the nucleolar protein CCDC137. CCDC137 degradation is conserved among pandemic HIV-1 and related SIVcpz/SIVgor Vpr variants, is triggered by genomic insults that activate a nucleolar ATR pathway (similar to camptothecin), and correlates with redistribution of nucleolar proteins, altered nucleolar morphology, and repressed ribosome biogenesis. CCDC137 degradation does not correlate with Vpr-induced G2/M arrest.\",\n      \"method\": \"Vpr functional genetics, ATR pathway inhibition, nucleolar protein localization assays, ribosome biogenesis assays, comparison across Vpr variants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetics, inhibition, localization, biogenesis assays), single lab\",\n      \"pmids\": [\"40530693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC137 knockdown in bladder cancer cells results in decreased expression of stearoyl-CoA desaturase (SCD), a key lipid metabolic enzyme, suggesting CCDC137 regulates lipid metabolism via SCD to promote bladder cancer progression.\",\n      \"method\": \"RNA sequencing, RT-PCR, western blot, CCK8, clonogenic, wound healing, Transwell assays, subcutaneous xenograft models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, downstream correlation between CCDC137 KD and SCD levels without direct mechanistic link established\",\n      \"pmids\": [\"40993629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC137 interacts with DGCR8 and promotes aerobic glycolysis in hepatocellular carcinoma through activation of the AKT/mTOR signaling pathway.\",\n      \"method\": \"Bioinformatics, functional cell assays, western blot, Co-IP (implied by interaction claim)\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanism described as potential/may-be with limited direct mechanistic validation reported in abstract\",\n      \"pmids\": [\"41029756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCDC137 interacts with S100A6 protein via co-immunoprecipitation, significantly enhancing S100A6 protein stability. Stabilized S100A6 in turn activates the PI3K/AKT signaling pathway, driving acute myeloid leukemia cell proliferation and cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), protein stability assays, functional proliferation and cell cycle experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with protein stability functional follow-up, single lab, two orthogonal methods\",\n      \"pmids\": [\"41964482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCDC137 activates the AKT/mTOR signaling pathway in sorafenib-resistant HCC cells; CCDC137 knockdown suppresses this pathway, while overexpression enhances sorafenib resistance. AKT inhibition with MK2206 reverses CCDC137-driven resistance.\",\n      \"method\": \"Western blot, knockdown/overexpression experiments, pharmacological AKT inhibition, in vitro cell viability and apoptosis assays\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway activation confirmed by western blot but upstream mechanism linking CCDC137 to AKT not directly established\",\n      \"pmids\": [\"41632344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK12 orchestrates transcription of SE-associated CCDC137 as an oncogenic gene in colorectal cancer; CDK12 inhibition preferentially represses CCDC137 transcription, reducing cellular survival, proliferation, and stemness, and ultimately liver metastasis.\",\n      \"method\": \"shRNA knockdown, selective CDK12 inhibitor (SR-4835), RNA sequencing, super-enhancer landscape integration, in vitro and in vivo assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq integrated with SE landscape, functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36254394\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC137 is a nucleolar RNA-binding protein that, in cancer contexts, binds specific mRNAs (FOXM1, JTV1, LASP1, FLOT2) to promote their cytoplasmic localization via interaction with DGCR8, forms a nuclear complex with LZTS2 and β-TrCP to drive K48-linked ubiquitination of LZTS2 at K467 activating β-catenin and AKT, stabilizes S100A6 to engage PI3K/AKT, and in normal biology serves as a sensor of nucleolar stress whose degradation is triggered by an ATR-dependent pathway in response to DNA damage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCDC137 is a nucleolar protein that has emerged primarily as an oncogenic effector across multiple cancers, where it converges on AKT-axis signaling to drive proliferation and disease progression [#0, #2]. As an RNA-binding protein, it binds a defined set of mRNAs (FOXM1, JTV1, LASP1, FLOT2) and, through interaction with the microprocessor protein DGCR8, promotes their cytoplasmic localization and elevated protein output, thereby activating AKT signaling in hepatocellular carcinoma [#0, #1]. In a distinct nuclear function, CCDC137 binds the \\u03b2-catenin negative regulator LZTS2 and recruits the E3 ligase \\u03b2-TrCP to catalyze K48-linked polyubiquitination of LZTS2 at lysine 467 via its 1\\u201375 domain, triggering AKT phosphorylation and \\u03b2-catenin pathway activation [#2]. It also acts as a protein stabilizer, binding S100A6 to enhance its stability and engage PI3K/AKT signaling in acute myeloid leukemia [#6]. In normal biology, CCDC137 behaves as a nucleolar stress sensor: HIV Vpr and genotoxic insults activate an ATR-dependent nucleolar pathway that drives its degradation, accompanied by nucleolar protein redistribution and repressed ribosome biogenesis [#3]. Its transcription is itself driven by CDK12 through super-enhancer regulation in colorectal cancer [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Established how CCDC137 expression is controlled, identifying it as a super-enhancer-associated oncogenic target of CDK12 transcriptional regulation.\",\n      \"evidence\": \"shRNA knockdown, selective CDK12 inhibitor (SR-4835), RNA-seq integrated with super-enhancer landscape, and in vivo metastasis assays in colorectal cancer\",\n      \"pmids\": [\"36254394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address the molecular function of the CCDC137 protein itself\", \"Mechanism by which CCDC137 supports survival/stemness downstream not defined here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CCDC137 as an RNA-binding protein that uses DGCR8 to redirect specific mRNAs to the cytoplasm, providing a mechanistic basis for its activation of AKT signaling.\",\n      \"evidence\": \"APOBEC1-mediated RNA profiling, Co-IP with DGCR8, mRNA localization assays, and in vitro/in vivo HCC models\",\n      \"pmids\": [\"37542342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding domain of CCDC137 not mapped\", \"How DGCR8 is repurposed from microprocessor to mRNA-localization role mechanistically unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a separate nuclear scaffolding function in which CCDC137 directs ubiquitin-mediated degradation of a \\u03b2-catenin antagonist, linking it to \\u03b2-catenin/AKT activation.\",\n      \"evidence\": \"Reciprocal Co-IP, site-specific (K467) ubiquitination mapping, domain deletion (1\\u201375), and peptide disruption in HCC organoids and PDX models\",\n      \"pmids\": [\"38918619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CCDC137 selects LZTS2 as substrate-presenting partner not defined\", \"Relationship between this nuclear function and the RNA-binding function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified CCDC137 as a target of nucleolar stress in normal biology, degraded through an ATR-dependent pathway upon HIV Vpr expression or genotoxic insult.\",\n      \"evidence\": \"Vpr functional genetics, ATR pathway inhibition, nucleolar localization and ribosome biogenesis assays, comparison across Vpr variants\",\n      \"pmids\": [\"40530693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase mediating CCDC137 degradation not identified\", \"Whether CCDC137 loss is cause or consequence of nucleolar disruption not resolved\", \"Degradation uncoupled from G2/M arrest but functional consequence of loss unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the protein-stabilizing mode of CCDC137 to S100A6, connecting it to PI3K/AKT-driven proliferation in acute myeloid leukemia.\",\n      \"evidence\": \"Co-IP, protein stability assays, and proliferation/cell-cycle functional experiments\",\n      \"pmids\": [\"41964482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of S100A6 stabilization (e.g. blocking degradation) not detailed\", \"Whether interaction is direct not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CCDC137's nucleolar localization and stress-sensor role mechanistically relate to its cytoplasmic oncogenic functions, and whether a single biochemical activity underlies its RNA-binding, ubiquitin-scaffolding, and protein-stabilizing roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CCDC137 or its functional domains beyond the 1\\u201375 region\", \"No unifying biochemical activity defined across reported functions\", \"Lipid-metabolism (SCD) and AKT/mTOR roles rest on correlative single-lab data\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DGCR8\", \"LZTS2\", \"BTRC\", \"S100A6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}