{"gene":"IGF2BP2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1999,"finding":"IGF2BP2 (IMP2) belongs to a family of three IGF-II mRNA-binding proteins (IMPs/IGF2BP1/2/3) that bind the 5' UTR of IGF-II leader 3 mRNA through two RNA recognition motifs and four KH domains, causing dose-dependent translational repression of IGF-II leader 3 mRNA; the proteins localize to subcytoplasmic domains in a growth-dependent and cell-specific manner.","method":"RNA binding assays, luciferase reporter translational repression assay, subcellular localization by immunofluorescence, developmental expression profiling in mouse embryos","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding, functional reporter assay, multiple orthogonal methods in a foundational study","pmids":["9891060"],"is_preprint":false},{"year":2018,"finding":"IGF2BP1/2/3 function as m6A readers that recognize the GG(m6A)C consensus sequence on thousands of mRNA targets via their KH domains; unlike YTHDF2, IGF2BPs promote mRNA stability and storage (e.g., MYC mRNA) in an m6A-dependent manner under normal and stress conditions, enhancing translation output.","method":"m6A-seq, PAR-CLIP, RNA immunoprecipitation, mRNA stability assays, KH domain mutagenesis, polysome profiling, loss-of-function in cancer cell lines","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis and functional validation, high citation count indicating broad replication","pmids":["29476152"],"is_preprint":false},{"year":2019,"finding":"IGF2BP2 acts downstream of METTL3-mediated m6A methylation to stabilize SOX2 mRNA by recognizing m6A marks in the coding sequence (CDS) region of SOX2 transcripts, preventing SOX2 mRNA degradation in colorectal carcinoma cells.","method":"MeRIP-seq, RNA immunoprecipitation, RNA pull-down, RNA stability assay, knockdown/overexpression in CRC cell lines and PDX models","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — reciprocal RIP, RNA stability assay, in vivo PDX validation, multiple orthogonal methods","pmids":["31230592"],"is_preprint":false},{"year":2021,"finding":"circNDUFB2 functions as a scaffold that enhances interaction between the E3 ubiquitin ligase TRIM25 and IGF2BP proteins (including IGF2BP2), forming a TRIM25/circNDUFB2/IGF2BPs ternary complex that promotes ubiquitination and proteasomal degradation of IGF2BPs; this effect is enhanced by m6A modification of circNDUFB2.","method":"Co-immunoprecipitation, ubiquitination assays, protein stability assays, m6A modification analysis, loss-of-function in NSCLC cell lines and mouse models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and functional degradation assays with in vivo validation, but IGF2BP2-specific effects not fully separated from IGF2BP1/3","pmids":["33436560"],"is_preprint":false},{"year":2015,"finding":"IGF2BP2 was identified as an IMP2-2/p62 splice variant that, when overexpressed in mouse liver, promotes hepatocarcinogenesis through DLK1-dependent activation of RAC1 GTPase, stimulating NADPH oxidase and elevating reactive oxygen species production.","method":"Transgenic mouse overexpression, DEN-induced carcinogenesis model, aCGH, siRNA knockdown in HepG2 cells, ROS measurement, inflammatory cytokine profiling","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo transgenic model with mechanistic follow-up via siRNA epistasis; specific to IGF2BP2-2 splice variant","pmids":["26426686"],"is_preprint":false}],"current_model":"IGF2BP2 is an mRNA-binding protein with two RRM and four KH domains that acts as an m6A reader (recognizing GG(m6A)C motifs) to stabilize and promote translation of target mRNAs such as MYC and SOX2; it was originally identified as a translational repressor of IGF-II leader 3 mRNA and localizes to subcytoplasmic granules, with its stability regulated by TRIM25-mediated ubiquitination scaffolded by circNDUFB2."},"narrative":{"teleology":[{"year":1999,"claim":"The discovery that IGF2BP2 binds the 5′ UTR of IGF-II leader 3 mRNA and represses its translation established IGF2BP2 as a post-transcriptional regulator with defined RNA-binding domain architecture (two RRMs and four KH domains) and subcytoplasmic localization.","evidence":"RNA binding assays, luciferase reporter translational repression, immunofluorescence in multiple cell types and mouse embryos","pmids":["9891060"],"confidence":"High","gaps":["Endogenous target repertoire beyond IGF-II mRNA was unknown","Mechanism of subcytoplasmic granule localization was not defined","Relative contributions of RRM versus KH domains to target selectivity were unresolved"]},{"year":2015,"claim":"A liver-specific overexpression model revealed that the IMP2-2/p62 splice variant of IGF2BP2 drives hepatocarcinogenesis through a DLK1–RAC1–NADPH oxidase–ROS axis, demonstrating that IGF2BP2 dysregulation has oncogenic consequences beyond direct translational control.","evidence":"Transgenic mouse liver overexpression, DEN-induced carcinogenesis, siRNA epistasis in HepG2 cells, ROS measurement","pmids":["26426686"],"confidence":"Medium","gaps":["Findings are specific to the IMP2-2 splice variant; contribution of full-length IGF2BP2 to this pathway is unclear","Direct RNA targets mediating DLK1 upregulation were not identified","Whether the ROS-promoting activity operates via m6A-dependent mRNA stabilization was not tested"]},{"year":2018,"claim":"Genome-wide identification of IGF2BP2 as an m6A reader that recognizes GG(m6A)C motifs through its KH domains fundamentally reframed the protein from a single-target translational repressor to a broad mRNA stabilizer that enhances translation of thousands of targets including MYC.","evidence":"m6A-seq, PAR-CLIP, RNA immunoprecipitation, KH domain mutagenesis, polysome profiling, mRNA stability assays in cancer cell lines","pmids":["29476152"],"confidence":"High","gaps":["Structural basis of m6A recognition by KH domains was not resolved","Context-dependent switching between translational repression and mRNA stabilization modes was not explained","Individual contributions of IGF2BP2 versus IGF2BP1/3 to shared target mRNAs were not fully delineated"]},{"year":2019,"claim":"Demonstration that IGF2BP2 stabilizes SOX2 mRNA by reading METTL3-deposited m6A marks in the coding sequence extended the m6A-reader model to a specific stemness-associated target in colorectal cancer, confirming the functional link between epitranscriptomic writing and IGF2BP2-mediated mRNA stabilization.","evidence":"MeRIP-seq, reciprocal RIP, RNA pull-down, RNA stability assay, knockdown/overexpression in CRC cell lines and PDX models","pmids":["31230592"],"confidence":"High","gaps":["Whether IGF2BP2 binding to CDS m6A sites involves distinct recognition geometry compared to 3′ UTR sites was not addressed","Relative importance of IGF2BP2-SOX2 axis versus other m6A readers in maintaining stemness was not resolved"]},{"year":2021,"claim":"Discovery that circNDUFB2 scaffolds TRIM25-mediated ubiquitination and proteasomal degradation of IGF2BP2 revealed a regulatory layer controlling IGF2BP2 protein abundance, linking circular RNA biology and m6A modification to IGF2BP2 turnover.","evidence":"Co-immunoprecipitation, ubiquitination assays, protein stability assays, m6A modification analysis in NSCLC cell lines and mouse models","pmids":["33436560"],"confidence":"Medium","gaps":["IGF2BP2-specific versus IGF2BP1/3 effects were not fully separated in this study","TRIM25 ubiquitination sites on IGF2BP2 were not mapped","Whether other E3 ligases regulate IGF2BP2 stability independently of circNDUFB2 is unknown"]},{"year":null,"claim":"The structural basis for m6A recognition by IGF2BP2's KH domains, the rules governing context-dependent switching between translational repression and mRNA stabilization, and the full repertoire of physiological (non-oncogenic) functions of IGF2BP2 remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of IGF2BP2 KH domains bound to m6A-containing RNA","Mechanism by which IGF2BP2 switches from translational repression (IGF-II) to mRNA stabilization (MYC, SOX2) is undefined","Physiological in vivo roles via conditional knockout models remain largely unexplored in the available literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]}],"complexes":[],"partners":["TRIM25","METTL3"],"other_free_text":[]},"mechanistic_narrative":"IGF2BP2 is an RNA-binding protein containing two RRM and four KH domains that regulates mRNA fate by binding target transcripts and modulating their stability and translation. Originally identified as a translational repressor of IGF-II leader 3 mRNA that localizes to subcytoplasmic granules in a growth-dependent manner [PMID:9891060], IGF2BP2 was subsequently shown to function as an N6-methyladenosine (m6A) reader that recognizes GG(m6A)C motifs via its KH domains, promoting stability and translational output of thousands of mRNA targets including MYC [PMID:29476152] and SOX2 [PMID:31230592]. IGF2BP2 protein levels are regulated by TRIM25-mediated ubiquitination scaffolded by the circular RNA circNDUFB2, which promotes its proteasomal degradation [PMID:33436560]."},"prefetch_data":{"uniprot":{"accession":"Q9Y6M1","full_name":"Insulin-like growth factor 2 mRNA-binding protein 2","aliases":["Hepatocellular carcinoma autoantigen p62","IGF-II mRNA-binding protein 2","VICKZ family member 2"],"length_aa":599,"mass_kda":66.1,"function":"RNA-binding factor that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs). This transcript 'caging' into mRNPs allows mRNA transport and transient storage. It also modulates the rate and location at which target transcripts encounter the translational apparatus and shields them from endonuclease attacks or microRNA-mediated degradation (By similarity). Preferentially binds to N6-methyladenosine (m6A)-containing mRNAs and increases their stability (PubMed:29476152). Binds to the 5'-UTR of the insulin-like growth factor 2 (IGF2) mRNAs (PubMed:9891060). Binding is isoform-specific. Binds to beta-actin/ACTB and MYC transcripts. Increases MYC mRNA stability by binding to the coding region instability determinant (CRD) and binding is enhanced by m6A-modification of the CRD (PubMed:29476152)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, P-body; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9Y6M1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF2BP2","classification":"Not Classified","n_dependent_lines":70,"n_total_lines":1208,"dependency_fraction":0.057947019867549666},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLTA","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"IGF2BP1","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IGF2BP2","total_profiled":1310},"omim":[{"mim_id":"613303","title":"AlkB HOMOLOG 5, RNA DEMETHYLASE; ALKBH5","url":"https://www.omim.org/entry/613303"},{"mim_id":"608289","title":"INSULIN-LIKE GROWTH FACTOR 2 mRNA-BINDING PROTEIN 2; IGF2BP2","url":"https://www.omim.org/entry/608289"},{"mim_id":"608288","title":"INSULIN-LIKE GROWTH FACTOR 2 mRNA-BINDING PROTEIN 1; IGF2BP1","url":"https://www.omim.org/entry/608288"},{"mim_id":"600698","title":"HIGH MOBILITY GROUP AT-HOOK 2; HMGA2","url":"https://www.omim.org/entry/600698"},{"mim_id":"147470","title":"INSULIN-LIKE GROWTH FACTOR II; IGF2","url":"https://www.omim.org/entry/147470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IGF2BP2"},"hgnc":{"alias_symbol":["IMP-2","p62","P62"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6M1","domains":[{"cath_id":"3.30.70.330","chopping":"4-74","consensus_level":"high","plddt":84.9849,"start":4,"end":74},{"cath_id":"3.30.70.330","chopping":"84-155","consensus_level":"high","plddt":83.1088,"start":84,"end":155},{"cath_id":"3.30.310.210","chopping":"197-356","consensus_level":"medium","plddt":88.7897,"start":197,"end":356},{"cath_id":"3.30.310.210","chopping":"429-587","consensus_level":"medium","plddt":89.4014,"start":429,"end":587}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6M1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6M1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6M1-F1-predicted_aligned_error_v6.png","plddt_mean":77.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGF2BP2","jax_strain_url":"https://www.jax.org/strain/search?query=IGF2BP2"},"sequence":{"accession":"Q9Y6M1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6M1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6M1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6M1"}},"corpus_meta":[{"pmid":"20098416","id":"PMC_20098416","title":"PINK1/Parkin-mediated 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N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33436560","id":"PMC_33436560","title":"circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33436560","citation_count":478,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25231870","id":"PMC_25231870","title":"Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25231870","citation_count":445,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44532,"output_tokens":623,"usd":0.071471},"stage2":{"model":"claude-opus-4-6","input_tokens":3543,"output_tokens":682,"usd":0.052147},"total_usd":0.32975,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":57351,"output_tokens":1747,"usd":0.099129},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4832,"output_tokens":1887,"usd":0.107003}},"stage1_raw":"Looking at these 100 papers, I need to identify which ones are actually about IGF2BP2 (IGF2 mRNA-binding protein 2) versus SQSTM1/p62 (sequestosome 1). \n\nThe vast majority of these papers (papers 1-100) are about SQSTM1/p62, NOT IGF2BP2. The only paper that mentions IGF2BP2 is paper [40], which refers to \"IMP2-2/IGF2BP2-2/p62\" in the context of hepatocellular carcinoma - but this \"p62\" here is a different protein (the IMP2 splice variant), not SQSTM1/p62.\n\nPaper [40] is about IGF2BP2 (IMP2/p62 splice variant) and contains some mechanistic findings relevant to IGF2BP2.\n\nLet me extract what I can from paper [40] about IGF2BP2 specifically:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"The IGF2BP2 splice variant p62 (IMP2-2/IGF2BP2-2) promotes hepatocarcinogenesis by inducing expression and secretion of DLK1, which in turn activates RAC1 (a small Rho-GTPase), leading to NADPH oxidase activation and elevated reactive oxygen species (ROS) production; this oncogenic mechanism involves DLK1-dependent RAC1 induction and activation.\",\n      \"method\": \"Transgenic mouse overexpression model (DEN-induced HCC), siRNA knockdown, ROS measurement, aCGH for chromosomal aberrations, immunohistochemistry, cell line overexpression experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/OE with defined cellular phenotype and partial pathway placement in mouse model and cell lines, single lab\",\n      \"pmids\": [\"26426686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Based on the available corpus, IGF2BP2 (IMP2/p62 splice variant) promotes hepatocarcinogenesis through DLK1-dependent activation of RAC1 and NADPH oxidase-driven ROS production, leading to genomic instability and an aggressive tumor phenotype; however, the corpus is dominated by papers about the unrelated SQSTM1/p62 protein, leaving IGF2BP2 mechanistic characterization very limited in this dataset.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to classify each paper:\n\n**RETRIEVED PAPERS [1-100]**: These are almost entirely about p62/SQSTM1 (sequestosome 1), which is a completely different protein from IGF2BP2. The \"p62\" alias of IGF2BP2 (specifically IMP2-2/IGF2BP2-2) is mentioned in paper [40] (IMP2/p62 in HCC), but that paper describes the IGF2BP2 splice variant p62 — KEEP. All other papers [1-39, 41-100] are about SQSTM1/p62, not IGF2BP2 — EXCLUDE (alias collision).\n\n**ADDITIONAL PAPERS [1-30]**: These include papers clearly about IGF2BP2:\n- Papers [1-3, 5, 8-9, 13, 18, 21, 22, 20] — KEEP (directly about IGF2BP2 function or GWAS identifying IGF2BP2 locus — though GWAS papers are expression/association only)\n- Paper [27] circNDUFB2 — describes circRNA effect on IGF2BPs protein degradation via TRIM25 — KEEP (describes mechanism affecting IGF2BP2 protein)\n- Papers [4, 6, 7, 10, 11, 12, 14-17, 19, 23-26, 28-30] — large proteomics/interactome screens or GWAS — mostly association; some have mechanistic content touching IGF2BP2\n\nLet me focus on mechanistic findings:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"IGF2BP2 (IMP2) belongs to a family of three IGF-II mRNA-binding proteins (IMPs/IGF2BP1/2/3) that bind the 5' UTR of IGF-II leader 3 mRNA through two RNA recognition motifs and four KH domains, causing dose-dependent translational repression of IGF-II leader 3 mRNA; the proteins localize to subcytoplasmic domains in a growth-dependent and cell-specific manner.\",\n      \"method\": \"RNA binding assays, luciferase reporter translational repression assay, subcellular localization by immunofluorescence, developmental expression profiling in mouse embryos\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding, functional reporter assay, multiple orthogonal methods in a foundational study\",\n      \"pmids\": [\"9891060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGF2BP1/2/3 function as m6A readers that recognize the GG(m6A)C consensus sequence on thousands of mRNA targets via their KH domains; unlike YTHDF2, IGF2BPs promote mRNA stability and storage (e.g., MYC mRNA) in an m6A-dependent manner under normal and stress conditions, enhancing translation output.\",\n      \"method\": \"m6A-seq, PAR-CLIP, RNA immunoprecipitation, mRNA stability assays, KH domain mutagenesis, polysome profiling, loss-of-function in cancer cell lines\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis and functional validation, high citation count indicating broad replication\",\n      \"pmids\": [\"29476152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGF2BP2 acts downstream of METTL3-mediated m6A methylation to stabilize SOX2 mRNA by recognizing m6A marks in the coding sequence (CDS) region of SOX2 transcripts, preventing SOX2 mRNA degradation in colorectal carcinoma cells.\",\n      \"method\": \"MeRIP-seq, RNA immunoprecipitation, RNA pull-down, RNA stability assay, knockdown/overexpression in CRC cell lines and PDX models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal RIP, RNA stability assay, in vivo PDX validation, multiple orthogonal methods\",\n      \"pmids\": [\"31230592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"circNDUFB2 functions as a scaffold that enhances interaction between the E3 ubiquitin ligase TRIM25 and IGF2BP proteins (including IGF2BP2), forming a TRIM25/circNDUFB2/IGF2BPs ternary complex that promotes ubiquitination and proteasomal degradation of IGF2BPs; this effect is enhanced by m6A modification of circNDUFB2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, protein stability assays, m6A modification analysis, loss-of-function in NSCLC cell lines and mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional degradation assays with in vivo validation, but IGF2BP2-specific effects not fully separated from IGF2BP1/3\",\n      \"pmids\": [\"33436560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF2BP2 was identified as an IMP2-2/p62 splice variant that, when overexpressed in mouse liver, promotes hepatocarcinogenesis through DLK1-dependent activation of RAC1 GTPase, stimulating NADPH oxidase and elevating reactive oxygen species production.\",\n      \"method\": \"Transgenic mouse overexpression, DEN-induced carcinogenesis model, aCGH, siRNA knockdown in HepG2 cells, ROS measurement, inflammatory cytokine profiling\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo transgenic model with mechanistic follow-up via siRNA epistasis; specific to IGF2BP2-2 splice variant\",\n      \"pmids\": [\"26426686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2BP2 is an mRNA-binding protein with two RRM and four KH domains that acts as an m6A reader (recognizing GG(m6A)C motifs) to stabilize and promote translation of target mRNAs such as MYC and SOX2; it was originally identified as a translational repressor of IGF-II leader 3 mRNA and localizes to subcytoplasmic granules, with its stability regulated by TRIM25-mediated ubiquitination scaffolded by circNDUFB2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IGF2BP2 is an RNA-binding protein whose splice variant (IMP2-2/IGF2BP2-2) promotes hepatocarcinogenesis by inducing expression and secretion of DLK1, which activates RAC1 and NADPH oxidase to elevate reactive oxygen species production, driving genomic instability and an aggressive tumor phenotype [PMID:26426686]. Beyond this oncogenic axis in liver, the broader mechanistic characterization of IGF2BP2 in the primary experimental literature remains limited.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing how IGF2BP2 drives hepatocarcinogenesis revealed a DLK1–RAC1–NADPH oxidase–ROS axis through which the IGF2BP2-2 splice variant promotes genomic instability and aggressive tumor growth.\",\n      \"evidence\": \"Transgenic mouse overexpression with DEN-induced HCC, siRNA knockdown, ROS assays, aCGH, and cell line experiments\",\n      \"pmids\": [\"26426686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings derive from a single laboratory and have not been independently replicated\",\n        \"Direct RNA targets of IGF2BP2 that mediate DLK1 upregulation are not identified\",\n        \"Whether the full-length IGF2BP2-1 isoform shares this oncogenic mechanism is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct mRNA targets bound by IGF2BP2 that control DLK1 expression, the structural basis of IGF2BP2–RNA recognition in this context, and the relevance of this pathway outside hepatocellular carcinoma remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No CLIP or equivalent data identifying direct IGF2BP2 RNA targets in this pathway\",\n        \"No structural model of IGF2BP2 KH/RRM domains engaging DLK1 mRNA\",\n        \"Role of IGF2BP2 in non-hepatic cancers and normal physiology is poorly characterized in the available literature\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DLK1\", \"RAC1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IGF2BP2 is an RNA-binding protein containing two RRM and four KH domains that regulates mRNA fate by binding target transcripts and modulating their stability and translation. Originally identified as a translational repressor of IGF-II leader 3 mRNA that localizes to subcytoplasmic granules in a growth-dependent manner [PMID:9891060], IGF2BP2 was subsequently shown to function as an N6-methyladenosine (m6A) reader that recognizes GG(m6A)C motifs via its KH domains, promoting stability and translational output of thousands of mRNA targets including MYC [PMID:29476152] and SOX2 [PMID:31230592]. IGF2BP2 protein levels are regulated by TRIM25-mediated ubiquitination scaffolded by the circular RNA circNDUFB2, which promotes its proteasomal degradation [PMID:33436560].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The discovery that IGF2BP2 binds the 5′ UTR of IGF-II leader 3 mRNA and represses its translation established IGF2BP2 as a post-transcriptional regulator with defined RNA-binding domain architecture (two RRMs and four KH domains) and subcytoplasmic localization.\",\n      \"evidence\": \"RNA binding assays, luciferase reporter translational repression, immunofluorescence in multiple cell types and mouse embryos\",\n      \"pmids\": [\"9891060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous target repertoire beyond IGF-II mRNA was unknown\",\n        \"Mechanism of subcytoplasmic granule localization was not defined\",\n        \"Relative contributions of RRM versus KH domains to target selectivity were unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A liver-specific overexpression model revealed that the IMP2-2/p62 splice variant of IGF2BP2 drives hepatocarcinogenesis through a DLK1–RAC1–NADPH oxidase–ROS axis, demonstrating that IGF2BP2 dysregulation has oncogenic consequences beyond direct translational control.\",\n      \"evidence\": \"Transgenic mouse liver overexpression, DEN-induced carcinogenesis, siRNA epistasis in HepG2 cells, ROS measurement\",\n      \"pmids\": [\"26426686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings are specific to the IMP2-2 splice variant; contribution of full-length IGF2BP2 to this pathway is unclear\",\n        \"Direct RNA targets mediating DLK1 upregulation were not identified\",\n        \"Whether the ROS-promoting activity operates via m6A-dependent mRNA stabilization was not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genome-wide identification of IGF2BP2 as an m6A reader that recognizes GG(m6A)C motifs through its KH domains fundamentally reframed the protein from a single-target translational repressor to a broad mRNA stabilizer that enhances translation of thousands of targets including MYC.\",\n      \"evidence\": \"m6A-seq, PAR-CLIP, RNA immunoprecipitation, KH domain mutagenesis, polysome profiling, mRNA stability assays in cancer cell lines\",\n      \"pmids\": [\"29476152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of m6A recognition by KH domains was not resolved\",\n        \"Context-dependent switching between translational repression and mRNA stabilization modes was not explained\",\n        \"Individual contributions of IGF2BP2 versus IGF2BP1/3 to shared target mRNAs were not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that IGF2BP2 stabilizes SOX2 mRNA by reading METTL3-deposited m6A marks in the coding sequence extended the m6A-reader model to a specific stemness-associated target in colorectal cancer, confirming the functional link between epitranscriptomic writing and IGF2BP2-mediated mRNA stabilization.\",\n      \"evidence\": \"MeRIP-seq, reciprocal RIP, RNA pull-down, RNA stability assay, knockdown/overexpression in CRC cell lines and PDX models\",\n      \"pmids\": [\"31230592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IGF2BP2 binding to CDS m6A sites involves distinct recognition geometry compared to 3′ UTR sites was not addressed\",\n        \"Relative importance of IGF2BP2-SOX2 axis versus other m6A readers in maintaining stemness was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that circNDUFB2 scaffolds TRIM25-mediated ubiquitination and proteasomal degradation of IGF2BP2 revealed a regulatory layer controlling IGF2BP2 protein abundance, linking circular RNA biology and m6A modification to IGF2BP2 turnover.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, protein stability assays, m6A modification analysis in NSCLC cell lines and mouse models\",\n      \"pmids\": [\"33436560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"IGF2BP2-specific versus IGF2BP1/3 effects were not fully separated in this study\",\n        \"TRIM25 ubiquitination sites on IGF2BP2 were not mapped\",\n        \"Whether other E3 ligases regulate IGF2BP2 stability independently of circNDUFB2 is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for m6A recognition by IGF2BP2's KH domains, the rules governing context-dependent switching between translational repression and mRNA stabilization, and the full repertoire of physiological (non-oncogenic) functions of IGF2BP2 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of IGF2BP2 KH domains bound to m6A-containing RNA\",\n        \"Mechanism by which IGF2BP2 switches from translational repression (IGF-II) to mRNA stabilization (MYC, SOX2) is undefined\",\n        \"Physiological in vivo roles via conditional knockout models remain largely unexplored in the available literature\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRIM25\",\n      \"METTL3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}