{"gene":"IGF2BP3","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1999,"finding":"IGF2BP3 (IMP3) was identified as a member of a family of three IGF-II mRNA-binding proteins (IMPs) that bind the 5' UTR of translationally regulated IGF-II leader 3 mRNA but not the constitutively translated leader 4 mRNA, causing dose-dependent translational repression of IGF-II leader 3 mRNA. The proteins contain two RNA recognition motifs and four KH domains and localize to subcytoplasmic domains in a growth-dependent and cell-specific manner.","method":"RNA binding assays, luciferase reporter translational repression assay, immunolocalization, developmental expression analysis in mouse and human embryos","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — original biochemical characterization with multiple orthogonal methods; foundational paper with >600 citations","pmids":["9891060"],"is_preprint":false},{"year":2018,"finding":"IGF2BP1/2/3 function as a distinct family of m6A readers that recognize the consensus GG(m6A)C sequence on thousands of mRNA transcripts, promoting mRNA stability and storage (e.g., MYC mRNA) in an m6A-dependent manner under normal and stress conditions, in contrast to the decay-promoting YTHDF2 reader. The K homology (KH) domains of IGF2BPs are required for m6A recognition and are critical for their oncogenic functions.","method":"m6A-seq, PAR-CLIP, RIP, RNA stability assays, mutagenesis of KH domains, in vitro binding assays, functional cancer cell assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, replicated across paralogs, >2300 citations; foundational m6A reader paper","pmids":["29476152"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of IMP3 RRM12 (N-terminal tandem RNA recognition motifs) bound to short RNA sequences revealed that both RRM domains adopt canonical RRM topology with a unique spatial orientation relative to each other compared to other tandem RRM structures. Only RRM1 is directly involved in RNA binding and recognizes a dinucleotide sequence.","method":"X-ray crystallography, biochemical RNA-binding characterization","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional biochemical validation","pmids":["30135093"],"is_preprint":false},{"year":2014,"finding":"IMP3 (IGF2BP3) RNPs function as cytoplasmic 'safe houses' that protect oncogenic let-7 target mRNAs (including HMGA2 and LIN28B) from miRNA-directed mRNA decay. IMP3-containing granules are depleted of Ago1-4 and miRNAs, IMP3 dose-dependently increases HMGA2 mRNA levels, and let-7 antagomiRs render HMGA2 refractory to IMP3 stabilization. Removal of let-7 target sites eliminates IMP3-dependent stabilization.","method":"Transcriptome analysis of cancer data, cytoplasmic granule fractionation, RIP, let-7 antagomiR experiments, deletion of 3'UTR let-7 binding sites, IMP1-deficient mouse embryo analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic (let-7 site deletion, IMP1-KO embryos) and biochemical (RIP, fractionation)","pmids":["24703842"],"is_preprint":false},{"year":2016,"finding":"IGF2BP3 (IMP3) is specifically overexpressed in MLL-rearranged B-ALL and is required for survival of B-ALL cell lines (knockdown causes decreased proliferation and increased apoptosis). CLIP-seq identified oncogenes MYC and CDK6 as direct IGF2BP3 targets regulated via 3'UTR binding elements. Enforced IGF2BP3 expression in murine BM cells enhanced Myc and Cdk6 expression, promoted hematopoietic stem/progenitor cell proliferation, and skewed development to B cell/myeloid lineage.","method":"CLIP-seq, knockdown/overexpression in cell lines and mouse BM transplant, 3'UTR reporter assays, mRNA expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — CLIP-seq identification of direct targets combined with in vivo mouse model and functional validation","pmids":["26974154"],"is_preprint":false},{"year":2016,"finding":"IMP3 (IGF2BP3) associates with circRNAs to form circRNA-protein complexes (circRNPs) of distinct sizes in mammalian cells. A specific set of IMP3-associated circRNAs was identified by combining RNA-seq of IMP3-co-immunoprecipitated RNA with filtering for circular-junction reads, defining a subfamily of circRNPs.","method":"Glycerol gradient centrifugation, polysome gradient fractionation, RNA-seq of immunoprecipitated RNA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical fractionation plus RNA-seq, single lab, novel finding","pmids":["27510448"],"is_preprint":false},{"year":2016,"finding":"IMP-3 (IGF2BP3) and its protein partners ILF3/NF90 and PTBP1 bind to the 3'UTRs of cyclin D1 and D3 mRNAs and protect them from translational repression induced by miRNA-dependent recruitment of the AGO2/GW182 complex. Knockdown of IMP-3 causes rapid decrease in cyclin protein levels while their mRNAs remain stable and polysome-associated but untranslated.","method":"RIP, polysome fractionation, knockdown experiments, protein level analysis","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in single lab; mechanistic dissection of translational protection","pmids":["27840950"],"is_preprint":false},{"year":2015,"finding":"IGF2BP3 destabilizes EIF4E-BP2 and MEIS3 mRNAs by interacting with ribonucleases XRN2 and exosome components (co-immunoprecipitation), thereby facilitating eIF4E-mediated translational activation. Depletion of EIF4E-BP2 partially rescues the growth retardation caused by IGF2BP3 knockdown, and IGF2BP3 depletion reduces phosphorylated (active) eIF4E. This was the first demonstration of IGF2BP3 as an RNA-destabilizing factor.","method":"RNA-seq, RIP-seq, co-immunoprecipitation with ribonucleases, mRNA stability assays, rescue experiments, analysis of human lung adenocarcinoma tissues","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; genetic epistasis rescue; clinical tissue correlation","pmids":["26522719"],"is_preprint":false},{"year":2017,"finding":"THADA gene fusion to LOC389473 (located 12 kb upstream of IGF2BP3) does not produce a chimeric protein but instead drives strong overexpression of full-length IGF2BP3 mRNA and protein in thyroid cancer, leading to increased IGF2 translation, activation of IGF1R/PI3K and MAPK signaling, and promotion of cell proliferation, invasion, and transformation. Inhibition of IGF1R blocks growth of IGF2BP3-overexpressing cells and tumors in vitro and in vivo.","method":"Whole-transcriptome and whole-genome sequencing, functional cell assays, IGF1R inhibitor treatment, in vivo xenograft","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genomic and functional validation, in vitro and in vivo evidence, mechanistic pathway identification","pmids":["28193878"],"is_preprint":false},{"year":2017,"finding":"IMP2 and IMP3 (IGF2BP2/3) are specifically overexpressed in triple-negative breast cancer, directly target progesterone receptor (PR) mRNA for destabilization through recruitment of the CCR4-NOT (CNOT1) complex, thereby suppressing transcription of miR-200a (which normally targets IMP2/3), forming a double-negative feedback loop that promotes EMT and metastasis.","method":"Knockdown/overexpression, cell invasion/invadopodia assays, mRNA stability assays, identification of CNOT1 complex recruitment, luciferase 3'UTR reporter, miRNA functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods; molecular mechanism dissected; single lab study","pmids":["29217458"],"is_preprint":false},{"year":2017,"finding":"IGF2BP3 directly associates with the deubiquitinase USP10 and attenuates its ability to stabilize p53 protein, promoting lung tumorigenesis. IGF2BP3 silencing increases p53 half-life and protein level and induces G0/G1 cell cycle arrest.","method":"Co-immunoprecipitation, protein half-life assays (cycloheximide chase), knockdown/overexpression, flow cytometry cell cycle analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and functional rescue; single lab","pmids":["29212181"],"is_preprint":false},{"year":2019,"finding":"Lin28b directly interacts with Igf2bp3 (proteomics and in situ analyses), and their co-expression in adult HSPCs reactivates fetal-like B-cell development more efficiently than either factor alone. In B-cell progenitors, Lin28b and Igf2bp3 jointly stabilize thousands of mRNAs (including Pax5 and Arid3a) by binding at the same sites, and Igf2bp3 mRNA itself is stabilized in an autoregulatory loop.","method":"Single-cell RNA-seq, proteomics, in situ analysis, CLIP/RIP-seq, in vivo mouse hematopoietic transplantation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — proteomics + in vivo functional validation + transcriptome-wide binding data; multiple orthogonal approaches","pmids":["31221665"],"is_preprint":false},{"year":2020,"finding":"Igf2bp3 is an essential regulator of maternal mRNA stability in zebrafish. Depletion of maternal igf2bp3 destabilizes maternal mRNAs prior to maternal-to-zygotic transition and causes severe developmental defects including abnormal cytoskeleton organization and cell division, while oogenesis and maternal mRNA levels in unfertilized eggs are normal. Igf2bp3 overexpression enhances stability of its target maternal mRNAs, and depletion or excess Igf2bp3 both impair embryogenesis.","method":"Maternal-specific mutant zebrafish, RNA-seq, Gene ontology analysis, mRNA stability assays, gain- and loss-of-function","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function (maternal mutant) plus gain-of-function with transcriptome-wide characterization in a vertebrate model","pmids":["32127635"],"is_preprint":false},{"year":2020,"finding":"DMDRMR (a lncRNA) binds IGF2BP3 to enhance its m6A-dependent activity on specific target mRNAs including CDK4, COL6A1, LAMA5, and FN1, stabilizing these transcripts and promoting G1-S transition and cell proliferation in clear cell renal cell carcinoma.","method":"RIP, RNA pulldown, m6A-seq, mRNA stability assays, functional cell and in vivo tumor assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + m6A-seq + functional validation; single lab study","pmids":["33293428"],"is_preprint":false},{"year":2021,"finding":"IGF2BP3 is critical for MLL-Af4-mediated leukemogenesis; deletion of Igf2bp3 significantly increases survival of mice with MLL-Af4-driven leukemia with minimal impact on baseline hematopoiesis. IGF2BP3 regulates a posttranscriptional operon including Hoxa locus genes and Ras pathway genes, controlling both steady-state mRNA levels and pre-mRNA splicing.","method":"Conditional genetic deletion in mouse leukemia model, survival analysis, leukemia-initiating cell functional assays, RNA-seq, CLIP-seq","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — genetic deletion in in vivo leukemia model with genome-wide RNA-seq/CLIP-seq; clean causal evidence","pmids":["34321607"],"is_preprint":false},{"year":2021,"finding":"circNDUFB2 acts as a scaffold to enhance the interaction between E3 ubiquitin ligase TRIM25 and IGF2BPs (including IGF2BP3), forming a TRIM25/circNDUFB2/IGF2BPs ternary complex that facilitates ubiquitination and proteasomal degradation of IGF2BPs; this effect is enhanced by m6A modification of circNDUFB2.","method":"RIP, RNA pulldown, co-immunoprecipitation, ubiquitination assays, m6A modification analysis, in vitro and in vivo functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods establishing the ternary complex and ubiquitination mechanism","pmids":["33436560"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A modification of PD-L1 mRNA is recognized by IGF2BP3, which stabilizes PD-L1 mRNA in breast cancer cells, promoting tumor immune escape. METTL3 knockdown abolishes m6A modification and reduces PD-L1 mRNA stabilization; IGF2BP3 knockdown or METTL3 inhibition enhances anti-tumor T cell activity both in vitro and in vivo.","method":"MeRIP-seq, epitranscriptomic microarray, MeRIP-qPCR, RIP-qPCR, mouse xenograft models, tissue microarray","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — MeRIP-seq + RIP-qPCR + in vivo validation; multiple methods establishing the METTL3/m6A/IGF2BP3/PD-L1 axis","pmids":["35197058"],"is_preprint":false},{"year":2022,"finding":"The m6A reader IGF2BP3 enhances stability of m6A-modified RCC2 mRNA in an m6A-dependent manner in acute myeloid leukemia cells. IGF2BP3 knockdown dramatically suppresses AML cell survival, reduces proliferation, impairs apoptosis resistance, and attenuates leukemic capacity in vitro and in vivo.","method":"RIP, mRNA stability assays, m6A-dependent binding assays, knockdown/overexpression, in vivo mouse AML model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + stability assays + in vivo model; single lab","pmids":["35217832"],"is_preprint":false},{"year":2022,"finding":"IMP3 (IGF2BP3) promotes prostate cancer metastasis by physically binding HDAC4 mRNA and enhancing its stability, thereby activating ERK signaling and inducing EMT. This is one of two parallel axes by which hsa_circ_0003258 promotes metastasis, the other being miR-653-5p sponging.","method":"RNA pulldown, RIP, Western blot, rescue experiments, in vitro and in vivo metastasis assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 3 — RIP/pulldown with functional rescue; single lab","pmids":["34986849"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 desensitizes lung adenocarcinoma cells to ferroptosis in an m6A reading domain-dependent manner by binding m6A-methylated mRNAs encoding anti-ferroptotic factors (GPX4, SLC3A2, ACSL3, FTH1), stabilizing these transcripts and sustaining anti-ferroptotic protein levels.","method":"m6A reader domain mutagenesis, RIP, mRNA stability assays, ferroptosis markers measurement, clinical specimen correlation","journal":"Materials today. Bio","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis + RIP + stability assays; single lab","pmids":["36457846"],"is_preprint":false},{"year":2022,"finding":"circNEIL3 stabilizes IGF2BP3 protein by preventing HECTD4-mediated ubiquitination of IGF2BP3, thereby protecting its oncogenic function in glioma. Additionally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and delivered to tumor-associated macrophages where it similarly stabilizes IGF2BP3 to promote immunosuppressive polarization.","method":"RNA pulldown, mass spectrometry, RIP, luciferase reporter, co-immunoprecipitation, ubiquitination assays, exosome characterization","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods; identifies HECTD4 as ubiquitin ligase for IGF2BP3","pmids":["35031058"],"is_preprint":false},{"year":2022,"finding":"TRIM25 E3 ubiquitin ligase promotes ubiquitination and degradation of IGF2BP3, and this process is competitively inhibited by circNFATC3 which binds IGF2BP3 in the cytoplasm, preventing TRIM25-mediated ubiquitination and thereby enhancing IGF2BP3 stability and its regulatory activity on CCND1 mRNA in gastric cancer.","method":"RIP, RNA-FISH/IF, co-immunoprecipitation, ubiquitin assays, rescue experiments, in vivo tumor model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods; identifies TRIM25 as E3 ligase for IGF2BP3","pmids":["37340423"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 recognizes m6A-modified minichromosome maintenance complex component MCM5 mRNAs to stabilize them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizing NICD1 and overactivating Notch signaling to induce partial EMT in lung adenocarcinoma.","method":"RIP, MeRIP-seq, mRNA stability assays, co-immunoprecipitation, SIRT1 deacetylation assays, functional EMT assays, clinical specimen analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods across the IGF2BP3/MCM5/SIRT1/NICD1 axis; single lab","pmids":["37171793"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 stabilizes COX6B2 mRNA by binding to its 3'-UTR in an m6A-dependent manner, increasing oxidative phosphorylation (OXPHOS) activity, and thereby driving acquired resistance to EGFR tyrosine kinase inhibitors. The IGF2BP3-COX6B2 axis also regulates nicotinamide metabolism to further alter OXPHOS and promote resistance.","method":"RIP, MeRIP analysis, mRNA stability assays, OXPHOS metabolic assays, siRNA knockdown, patient-derived xenograft model, OXPHOS inhibitor treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — RIP + mRNA stability + metabolic assays + PDX model; multiple orthogonal approaches in single lab","pmids":["37061993"],"is_preprint":false},{"year":2023,"finding":"circRARS binds to the KH1-KH2 domains of IGF2BP3 (via a 12-nt sequence GUCUUCCAGCAA) to enhance IGF2BP3's m6A modification recognition activity, and the IGF2BP3/circRARS complex recruits stabilizer proteins HuR, Matrin3, and pAbPC1 to increase mRNA stability of target genes (CAPN15, CD44, HMGA2, TNRC6A, ZMIZ2) in an m6A-dependent manner.","method":"RIP, RNA pulldown, domain mapping, m6A binding assays, functional in vitro and in vivo assays, identification of specific binding sequence","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — domain-level binding specificity mapped plus m6A-dependent functional validation; single lab","pmids":["38073586"],"is_preprint":false},{"year":2023,"finding":"Parkin E3 ubiquitin ligase directly interacts with IGF2BP3 and promotes its proteasomal degradation by ubiquitinating it; the ubiquitination site was mapped to K213 in the first KH domain of IGF2BP3. IGF2BP3 K213 mutation abolishes its oncogenic m6A reader function and inactivates PI3K and MAPK signaling in cervical cancer.","method":"Co-immunoprecipitation, in vivo and in vitro ubiquitination assays, mass spectrometry ubiquitination site mapping, RNA-IP, xenograft mouse model","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 — ubiquitination site precisely mapped by mass spectrometry, functional consequence of site mutation validated; multiple orthogonal methods","pmids":["37877353"],"is_preprint":false},{"year":2023,"finding":"USP11 deubiquitinase directly interacts with IGF2BP3 and protects it from proteasomal degradation via deubiquitination, as demonstrated by co-immunoprecipitation and ubiquitination assays. IGF2BP3 overexpression reverses the decrease in colorectal cancer cell proliferation, migration, and invasion caused by USP11 knockdown.","method":"Co-immunoprecipitation, ubiquitination assays, Western blotting, rescue experiments, in vivo tumor assays","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and ubiquitination assays with functional rescue; single lab","pmids":["33594305"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 promotes mRNA degradation through binding internal m7G-modified mRNAs. IGF2BP family proteins preferentially bind internal mRNA m7G, but with distinct functional consequences: IGF2BP3 binding promotes degradation of m7G target transcripts (including TP53 mRNA at its 3'UTR in glioblastoma), whereas IGF2BP1 prefers m6A to stabilize transcripts. Modulating IGF2BP3 or site-specific m7G targeting via dCas13b affects TP53 mRNA half-life, cancer progression, and chemosensitivity.","method":"m7G-modified RNA pull-down, binding assays, mRNA stability (half-life) assays, dCas13b site-specific targeting, functional cancer cell assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — novel mechanistic finding with in vitro binding, site-specific dCas13b functional validation, and in vivo relevance; multiple methods","pmids":["39198433"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 stabilizes EGFR mRNA in an m6A-dependent manner (cooperating with METTL14) and promotes EGFR pathway activation and cetuximab resistance in colorectal cancer.","method":"RIP, MeRIP, mRNA stability assays, functional cell and in vivo assays, clinical specimen analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + MeRIP + stability assays; single lab","pmids":["37658049"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 binds SLIT2 mRNA and destabilizes m6A-methylated SLIT2 mRNA, impairing SLIT2/ROBO1 signaling and consequently activating PI3K/AKT and MEK/ERK pathways to promote triple-negative breast cancer migration and invasion.","method":"RIP, mRNA stability assays, m6A modification analysis, functional migration/invasion assays, in vivo metastasis model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + stability + m6A; single lab; demonstrates m6A-dependent destabilization (opposite polarity to canonical IGF2BP3 stabilization)","pmids":["36250924"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 promotes myocardial regeneration by binding and stabilizing MMP3 mRNA through m6A modification interaction. IGF2BP3 expression progressively decreases postnatally but is re-induced after cardiac injury. MMP3 acts as a downstream effector of IGF2BP3 to regulate cardiomyocyte proliferation, and IGF2BP3 promotes cardiac function recovery after myocardial infarction in mice.","method":"Gain- and loss-of-function in vitro and in vivo (mouse MI model), RIP, mRNA stability assays, m6A analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse cardiac model with RIP and stability assays; single lab","pmids":["37188676"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 synergizes with NONO to promote exon 6 skipping in DLG1 pre-mRNA in an m6A-dependent manner, and IGF2BP3 disrupts the binding of RBM14 to NONO, thereby relieving RBM14's inhibition of NONO-mediated alternative splicing in gallbladder cancer.","method":"RIP-seq, mRNA-seq, co-immunoprecipitation/mass spectrometry, alternative splicing analysis (PSI values), functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection of splicing regulation by IP/MS and RIP-seq; single lab","pmids":["38341127"],"is_preprint":false},{"year":2024,"finding":"In glioma, IGF2BP3 enhances expression of E3 ubiquitin ligase MIB1, promoting FTO (m6A demethylase) degradation via the ubiquitin-proteasome pathway, resulting in increased m6A-mediated CSF3 release and NET (neutrophil extracellular trap) formation, which impedes oncolytic virus replication.","method":"Functional assays, ubiquitin-proteasome pathway analysis, m6A analysis, in vivo mouse glioma models, BET inhibitor treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic chain established in vitro and in vivo; single lab","pmids":["38167409"],"is_preprint":false},{"year":2024,"finding":"Lactylation of IGF2BP3 (driven by increased glycolysis and lactate accumulation in lenvatinib-resistant HCC) is crucial for IGF2BP3 to capture PCK2 and NRF2 mRNAs and enhance their stability. The lactylated IGF2BP3 also increases SAM availability, fueling m6A methylation of PCK2 and NRF2 mRNAs, creating a positive feedback loop that reinforces drug resistance.","method":"Lactylation assays, RIP, MeRIP, mRNA stability assays, metabolomics, in vivo lenvatinib-resistant models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — novel PTM (lactylation) mechanistically linked to RNA binding function; multiple methods; single lab","pmids":["39450426"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 stabilizes HMGB1 mRNA by binding to it, promoting HMGB1 expression and bladder cancer progression; this relationship between HMGB1 mRNA and IGF2BP3 is also conserved in mammalian embryonic development where both genes decrease as development progresses. The IGF2BP3 gene is regulated by copy number gain/amplification, promoter hypomethylation, and miR-320a-3p.","method":"RIP, mRNA stability assays, bisulfite sequencing, luciferase reporter, xenograft mouse model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + stability assays + multiple regulatory mechanism analysis; single lab","pmids":["38504159"],"is_preprint":false},{"year":2024,"finding":"WTAP-mediated m6A modification of ULK1 mRNA enhances its stability in an IGF2BP3-dependent manner, leading to elevated ULK1 expression and enhanced mitophagy in epithelial ovarian cancer, contributing to disease progression.","method":"MeRIP, RIP, mRNA stability assays, functional mitophagy assays, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP + RIP + functional validation; single lab","pmids":["38286802"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 regulates SCD mRNA m6A modifications via an IGF2BP3-METTL14 complex, enhancing SCD mRNA stability to promote lipid metabolism, proliferation, and metastasis in cervical cancer.","method":"RNA-seq, RIP assay, MeRIP, lipid droplet/TG/fatty acid assays, in vivo nude mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + MeRIP + metabolic validation; single lab","pmids":["38355626"],"is_preprint":false},{"year":2024,"finding":"SENP1 mRNA 3'UTR is bound by IGF2BP3 in an m6A-dependent manner (MeRIP-qPCR and RIP-qPCR), enhancing SENP1 expression and stability in AML. IGF2BP3-stabilized SENP1 promotes AKT pathway activation via de-SUMOylation of HDAC2, which enhances EGFR transcription.","method":"CO-IP, MeRIP-qPCR, RIP-qPCR, RNA pulldown, SUMO assay, ChIP-qPCR, in vitro and in vivo AML models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays establishing the IGF2BP3/m6A/SENP1/HDAC2 axis; single lab","pmids":["38822351"],"is_preprint":false},{"year":2024,"finding":"RBM15 (m6A writer) mediates m6A modification of VEGFA mRNA, which is then recognized and stabilized by IGF2BP3, leading to enhanced VEGFA expression and HUVEC tube formation/migration. Knockdown of IGF2BP3 reduces VEGFA expression and inhibits tumor angiogenesis in HCC xenograft models.","method":"MeRIP-seq, RNA-seq, CLIP-seq, RIP, cell and molecular biology validation, HCC xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics plus functional validation; single lab","pmids":["39092767"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 binds MYLK mRNA in an m6A-dependent manner, extending its half-life and inhibiting ERK1/2 phosphorylation, thereby repressing MSC adipogenesis. IGF2BP3 overexpression in adipose tissue (via AAV) reduces body weight and improves insulin resistance in high-fat diet mice.","method":"RIP, mRNA stability assays, m6A-dependent binding validation, ERK signaling analysis, in vivo AAV delivery, metabolic phenotyping","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — RIP + stability + in vivo AAV model; single lab; demonstrates physiological role in metabolism","pmids":["38196046"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 recognizes m6A on mRNAs of key serine synthesis pathway (SSP) genes (ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the metabolic demands of AML cells and leukemia stem/initiating cells. CRISPR/Cas9 screen identified that IGF2BP3 depletion sensitizes AML cells to serine/glycine deprivation; combined IGF2BP3 silencing with dietary SG restriction potently inhibits AML in vitro and in vivo while sparing normal hematopoiesis.","method":"CRISPR/Cas9 screen, RIP, mRNA stability assays, metabolomics, dietary restriction in vivo mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — CRISPR screen + RIP + in vivo validation + metabolomics; multiple orthogonal approaches","pmids":["40328743"],"is_preprint":false},{"year":2014,"finding":"IGF2BP3 (IMP3) promotes trophoblast cell invasion and migration in placenta. IGF2BP3 is highly expressed in cytotrophoblast cells during early pregnancy and is reduced in the third trimester and in pre-eclamptic placentas. In vitro invasion/migration assays and ex vivo explant culture demonstrated that IGF2BP3 promotes trophoblast invasion.","method":"Immunohistochemistry in human placentas, in vitro invasion/migration assays, ex vivo explant culture model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional invasion assays in primary cells with clinical correlation; no defined molecular target in trophoblasts","pmids":["24457969"],"is_preprint":false},{"year":2017,"finding":"In CD44-positive fibroblasts, IGF2BP3 binds CD44 mRNA and enhances its expression, which increases IGF2 secretion by fibroblasts, stimulating breast cancer cell proliferation and paclitaxel resistance via Hedgehog signaling activation in breast cancer cells.","method":"Co-culture experiments, RIP for IGF2BP3-CD44 mRNA interaction, functional proliferation/drug resistance assays, Hedgehog pathway analysis","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 — RIP with functional co-culture assay; single lab; limited molecular mechanistic depth","pmids":["28523716"],"is_preprint":false},{"year":2020,"finding":"IMP3 (IGF2BP3) accelerates prostate cancer progression by increasing SMURF1 expression, which facilitates PTEN ubiquitination and degradation, activating the PI3K/AKT/mTOR signaling pathway.","method":"Immunoprecipitation/ubiquitination assays, Western blotting for PI3K/AKT/mTOR pathway, knockdown/overexpression, rescue experiments with SMURF1 silencing","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assays + pathway rescue; single lab; mechanism identified","pmids":["32938489"],"is_preprint":false}],"current_model":"IGF2BP3 is an oncofetal RNA-binding protein containing two RRM domains (RRM1 mediates RNA binding) and four KH domains (required for m6A recognition) that functions primarily as an m6A reader to stabilize thousands of target mRNAs by recognizing the GG(m6A)C consensus sequence; it can also destabilize mRNAs through interaction with ribonucleases (e.g., XRN2, exosome) or by binding internal m7G-modified mRNAs; its activity and stability are regulated by multiple post-translational mechanisms including ubiquitination by HECTD4, TRIM25, and Parkin (at K213 in the KH1 domain), deubiquitination by USP11, and lysine lactylation; it directly targets oncogenic transcripts including MYC, CDK6, HMGA2, RCC2, EGFR, COX6B2, and serine synthesis pathway genes, and cooperates with lncRNAs/circRNAs that modulate its activity or protect it from ubiquitin-mediated degradation, while its re-expression in cancer (often driven by promoter demethylation or gene fusion/amplification) drives tumor proliferation, metastasis, metabolic reprogramming, immune evasion, and drug resistance across multiple cancer types."},"narrative":{"teleology":[{"year":1999,"claim":"The initial characterization of IGF2BP3 as an IGF-II mRNA-binding protein with two RRM and four KH domains that represses IGF-II leader 3 mRNA translation established it as a developmentally regulated post-transcriptional regulator.","evidence":"RNA binding assays, luciferase translational reporter, immunolocalization in human/mouse embryos","pmids":["9891060"],"confidence":"High","gaps":["Endogenous target repertoire beyond IGF-II unknown","No structural detail of RNA recognition","Mechanism of translational repression not defined"]},{"year":2014,"claim":"The discovery that IGF2BP3-containing cytoplasmic granules exclude AGO/miRNAs and shield let-7 target mRNAs (HMGA2, LIN28B) from miRNA-mediated decay revealed a 'safe house' mechanism of mRNA stabilization distinct from direct translational control.","evidence":"Granule fractionation, RIP, let-7 antagomiR experiments, 3′UTR let-7 site deletion, IMP1-KO mouse embryos","pmids":["24703842"],"confidence":"High","gaps":["Composition of safe-house granules not fully defined","Whether miRNA exclusion is active or passive unclear","Applicability beyond let-7 targets not tested"]},{"year":2015,"claim":"Demonstrating that IGF2BP3 can destabilize mRNAs (EIF4E-BP2, MEIS3) by recruiting XRN2 and exosome components overturned the assumption that it exclusively stabilizes targets, revealing context-dependent polarity of its post-transcriptional effects.","evidence":"RNA-seq, RIP-seq, co-IP with ribonucleases, mRNA stability assays, rescue experiments in lung adenocarcinoma","pmids":["26522719"],"confidence":"High","gaps":["What determines stabilization versus destabilization for a given target","Whether ribonuclease recruitment requires cofactors","Structural basis of XRN2/exosome interaction unknown"]},{"year":2016,"claim":"CLIP-seq identification of MYC and CDK6 as direct IGF2BP3 targets in MLL-rearranged B-ALL, combined with in vivo mouse hematopoietic models, established IGF2BP3 as a functionally essential oncogene in leukemia with defined downstream effectors.","evidence":"CLIP-seq, 3′UTR reporters, mouse BM transplant, knockdown in B-ALL lines","pmids":["26974154"],"confidence":"High","gaps":["Mechanism of IGF2BP3 re-activation in MLL-rearranged leukemia not resolved","Relative contribution of MYC versus CDK6 to leukemogenesis not separated","Translational versus stability regulation on these targets not distinguished"]},{"year":2018,"claim":"The landmark identification of IGF2BP1/2/3 as a new class of m6A readers that stabilize thousands of m6A-marked mRNAs via their KH domains unified prior observations under an epitranscriptomic framework and distinguished IGF2BPs from decay-promoting YTHDF readers.","evidence":"m6A-seq, PAR-CLIP, RIP, KH domain mutagenesis, MYC mRNA stability assays","pmids":["29476152"],"confidence":"High","gaps":["How KH domains specifically recognize m6A versus unmethylated RNA structurally undefined","Whether all four KH domains contribute equally unknown","Relative m6A-dependent versus m6A-independent binding proportions unquantified"]},{"year":2018,"claim":"Crystal structure of the RRM1-RRM2 tandem revealed that only RRM1 contacts RNA via a dinucleotide recognition mode, with a unique inter-domain orientation, providing the first atomic-resolution view of IGF2BP3-RNA recognition.","evidence":"X-ray crystallography with biochemical RNA-binding validation","pmids":["30135093"],"confidence":"High","gaps":["No structure of KH domains or full-length protein","How RRM and KH domains cooperate on a single mRNA unknown","Structure of m6A-bound complex not determined"]},{"year":2019,"claim":"LIN28B and IGF2BP3 were shown to physically interact and co-stabilize thousands of mRNAs in fetal B-cell progenitors, jointly driving fetal-like lymphopoiesis more efficiently than either factor alone, revealing a cooperative post-transcriptional program in normal hematopoiesis.","evidence":"Proteomics, in situ analysis, CLIP/RIP-seq, in vivo mouse HSPC transplantation, scRNA-seq","pmids":["31221665"],"confidence":"High","gaps":["Whether LIN28B-IGF2BP3 interaction is direct or RNA-mediated not fully resolved","Autoregulatory loop mechanism not structurally characterized","Relevance to leukemia initiation not tested"]},{"year":2020,"claim":"Maternal-specific igf2bp3 deletion in zebrafish causing embryonic lethality through destabilization of maternal mRNAs established that IGF2BP3's mRNA-stabilizing function is essential for vertebrate embryogenesis, not only cancer.","evidence":"Maternal mutant zebrafish, RNA-seq, mRNA half-life measurements, gain- and loss-of-function","pmids":["32127635"],"confidence":"High","gaps":["Whether mammalian maternal-zygotic transition depends on IGF2BP3 similarly untested","Specific target mRNAs critical for cytokinesis not identified","Redundancy with IGF2BP1/2 in this context unknown"]},{"year":2021,"claim":"Genetic deletion of Igf2bp3 in an MLL-Af4 leukemia mouse model significantly extended survival with minimal effect on normal hematopoiesis, validating IGF2BP3 as a therapeutic target and revealing its regulation of Hoxa genes and Ras pathway mRNAs including pre-mRNA splicing.","evidence":"Conditional knockout in mouse MLL-Af4 leukemia model, CLIP-seq, RNA-seq, leukemia-initiating cell assays","pmids":["34321607"],"confidence":"High","gaps":["How IGF2BP3 regulates splicing mechanistically not defined","Whether pharmacological inhibition recapitulates genetic deletion unknown","Splicing versus stability contribution to leukemogenesis not separated"]},{"year":2021,"claim":"Identification of TRIM25 as an E3 ligase that ubiquitinates IGF2BP3 for proteasomal degradation—scaffolded by the circRNA circNDUFB2—established the first ubiquitin-dependent regulatory mechanism controlling IGF2BP3 protein turnover.","evidence":"RIP, RNA pulldown, co-IP, ubiquitination assays, m6A analysis, in vivo assays","pmids":["33436560"],"confidence":"High","gaps":["Specific ubiquitination sites by TRIM25 not mapped","Whether other circRNAs similarly scaffold E3 ligases for IGF2BP3 unknown","Physiological versus cancer-specific relevance of this pathway unclear"]},{"year":2022,"claim":"Multiple studies converged to define IGF2BP3's ubiquitin regulatory network: HECTD4 and Parkin (ubiquitination at K213 in KH1) promote degradation while USP11 deubiquitinates and stabilizes it, and circRNAs (circNEIL3, circNFATC3) competitively block ubiquitination, establishing IGF2BP3 protein level as a tightly controlled node.","evidence":"Co-IP, mass spectrometry site mapping (K213), in vitro/in vivo ubiquitination assays, circRNA binding competition, xenograft models","pmids":["37877353","35031058","37340423","33594305"],"confidence":"High","gaps":["Hierarchy among E3 ligases in different tissues not established","Whether K213 ubiquitination is the sole functional site unknown","Interplay between lactylation and ubiquitination at nearby residues not explored"]},{"year":2022,"claim":"IGF2BP3's m6A reader function was shown to stabilize PD-L1 mRNA downstream of METTL3, directly linking epitranscriptomic mRNA regulation to tumor immune evasion and providing a mechanistic basis for immune checkpoint resistance.","evidence":"MeRIP-seq, RIP-qPCR, METTL3/IGF2BP3 knockdown, T cell co-culture, mouse xenografts","pmids":["35197058"],"confidence":"High","gaps":["Whether IGF2BP3 stabilizes other immune checkpoint mRNAs not tested","Patient response to immunotherapy correlation not established","Structural basis of m6A-PD-L1 mRNA recognition unknown"]},{"year":2023,"claim":"The discovery that IGF2BP3 preferentially binds internal m7G-modified mRNAs and promotes their degradation (including TP53 mRNA) revealed a second epitranscriptomic reading modality with opposite functional polarity to its m6A reader activity.","evidence":"m7G-modified RNA pull-down, binding assays, dCas13b site-specific targeting, mRNA half-life assays in glioblastoma","pmids":["39198433"],"confidence":"High","gaps":["Structural basis for m7G versus m6A discrimination unknown","Genome-wide scope of m7G-dependent destabilization not mapped","Whether m6A and m7G marks on the same transcript compete for IGF2BP3 binding untested"]},{"year":2023,"claim":"CircRARS was found to bind IGF2BP3 KH1-KH2 domains via a specific 12-nt motif, enhancing m6A recognition and recruiting stabilizer proteins HuR, Matrin3, and pAbPC1, defining a circRNA-mediated mechanism that augments IGF2BP3's m6A reader activity.","evidence":"RIP, RNA pulldown, domain mapping, m6A binding assays, identification of GUCUUCCAGCAA binding motif","pmids":["38073586"],"confidence":"Medium","gaps":["Whether circRARS allosterically changes KH domain conformation or acts as a scaffold uncertain","Generalizability of this 12-nt motif to other circRNAs not tested","Stoichiometry of the circRARS/IGF2BP3/stabilizer complex unknown"]},{"year":2024,"claim":"Lysine lactylation of IGF2BP3 was identified as a glycolysis-driven post-translational modification that enhances its mRNA-binding capacity and creates a positive feedback loop with m6A methylation (via SAM availability), connecting metabolic state to epitranscriptomic regulation in drug-resistant HCC.","evidence":"Lactylation assays, RIP, MeRIP, metabolomics, lenvatinib-resistant in vivo models","pmids":["39450426"],"confidence":"Medium","gaps":["Specific lactylated residues on IGF2BP3 not mapped","Whether lactylation competes with ubiquitination at the same lysines unknown","Relevance beyond lenvatinib resistance not established"]},{"year":2024,"claim":"A CRISPR screen revealed that IGF2BP3 sustains the serine synthesis pathway by stabilizing m6A-marked ATF4, PHGDH, and PSAT1 mRNAs in AML, and combined IGF2BP3 depletion with dietary serine/glycine restriction potently suppressed leukemia while sparing normal hematopoiesis, defining a metabolic vulnerability.","evidence":"CRISPR/Cas9 screen, RIP, mRNA stability, metabolomics, dietary restriction in vivo AML models","pmids":["40328743"],"confidence":"High","gaps":["Whether this metabolic dependency extends to solid tumors unknown","Pharmacological IGF2BP3 inhibitor for clinical translation not available","Mechanism by which normal HSPCs compensate for IGF2BP3 loss unclear"]},{"year":null,"claim":"A full structural understanding of how IGF2BP3 discriminates m6A from m7G modifications, how its six RNA-binding domains cooperate on a single mRNA, and whether selective pharmacological inhibition can recapitulate the therapeutic window seen with genetic deletion remain major open questions.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length or KH-domain m6A-bound structure exists","No selective small-molecule IGF2BP3 inhibitor reported","Rules governing stabilization versus destabilization of individual target mRNAs undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,4,7,12,24,27]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,10,27,31]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3,21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,3,7,14,27,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,43,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,14,17,40]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[23,36,40]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,20,25]}],"complexes":[],"partners":["LIN28B","TRIM25","NONO","USP11","XRN2","PRKN","ILF3","PTBP1"],"other_free_text":[]},"mechanistic_narrative":"IGF2BP3 is an oncofetal RNA-binding protein that functions as a major N6-methyladenosine (m6A) reader, using its KH domains to recognize GG(m6A)C motifs on thousands of mRNA targets and predominantly stabilizing them—including MYC, CDK6, HMGA2, EGFR, PD-L1, and serine synthesis pathway transcripts—thereby promoting proliferation, immune evasion, metabolic reprogramming, and drug resistance across diverse cancers [PMID:29476152, PMID:26974154, PMID:35197058, PMID:40328743]. Beyond m6A-dependent stabilization, IGF2BP3 can destabilize specific mRNAs through interaction with ribonucleases XRN2 and the exosome or via recognition of internal m7G modifications, and it regulates alternative splicing in concert with NONO [PMID:26522719, PMID:39198433, PMID:38341127]. IGF2BP3 protein turnover is tightly controlled by ubiquitination through multiple E3 ligases (TRIM25, HECTD4, Parkin at K213) counterbalanced by USP11-mediated deubiquitination, while circRNAs (circNFATC3, circNEIL3, circRARS) and the post-translational modification lysine lactylation modulate its stability and RNA-binding activity [PMID:33436560, PMID:37877353, PMID:35031058, PMID:39450426]. During normal development, IGF2BP3 is essential for maternal mRNA stability during the zebrafish maternal-to-zygotic transition and cooperates with LIN28B to drive fetal-like B-cell lymphopoiesis, while its aberrant re-expression in adult tissues is a hallmark of MLL-rearranged leukemia and numerous solid tumors [PMID:32127635, PMID:31221665, PMID:34321607]."},"prefetch_data":{"uniprot":{"accession":"O00425","full_name":"Insulin-like growth factor 2 mRNA-binding protein 3","aliases":["IGF-II mRNA-binding protein 3","KH domain-containing protein overexpressed in cancer","hKOC","VICKZ family member 3"],"length_aa":579,"mass_kda":63.7,"function":"RNA-binding factor that may recruit 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. Preferentially binds to N6-methyladenosine (m6A)-containing mRNAs and increases their stability (PubMed:29476152). Binds to the 3'-UTR of CD44 mRNA and stabilizes it, hence promotes cell adhesion and invadopodia formation in cancer cells. 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). Binds to the 5'-UTR of the insulin-like growth factor 2 (IGF2) mRNAs","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, P-body; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/O00425/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF2BP3","classification":"Not 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IGF2BP1","url":"https://www.omim.org/entry/608288"},{"mim_id":"608259","title":"INSULIN-LIKE GROWTH FACTOR 2 mRNA-BINDING PROTEIN 3; IGF2BP3","url":"https://www.omim.org/entry/608259"},{"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":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":6.9},{"tissue":"placenta","ntpm":27.2}],"url":"https://www.proteinatlas.org/search/IGF2BP3"},"hgnc":{"alias_symbol":["IMP-3","CT98","IMP3"],"prev_symbol":[]},"alphafold":{"accession":"O00425","domains":[{"cath_id":"3.30.70.330","chopping":"1-71","consensus_level":"high","plddt":84.987,"start":1,"end":71},{"cath_id":"3.30.70.330","chopping":"81-152","consensus_level":"high","plddt":83.649,"start":81,"end":152},{"cath_id":"3.30.310.210","chopping":"197-354","consensus_level":"medium","plddt":87.6335,"start":197,"end":354},{"cath_id":"3.30.310.210","chopping":"405-565","consensus_level":"medium","plddt":86.3875,"start":405,"end":565}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00425","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00425-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00425-F1-predicted_aligned_error_v6.png","plddt_mean":77.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGF2BP3","jax_strain_url":"https://www.jax.org/strain/search?query=IGF2BP3"},"sequence":{"accession":"O00425","fasta_url":"https://rest.uniprot.org/uniprotkb/O00425.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00425/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00425"}},"corpus_meta":[{"pmid":"14671650","id":"PMC_14671650","title":"Design 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PD-L1 expression and tumor immune escape in breast cancer.\",\n      \"method\": \"MeRIP-seq, MeRIP-qPCR, RIP-qPCR, METTL3/IGF2BP3 knockdown with rescue experiments, xenograft models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MeRIP-seq, RIP-qPCR, KD/rescue, in vivo) in a single study with strong mechanistic evidence\",\n      \"pmids\": [\"35197058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circNEIL3 stabilizes IGF2BP3 protein by preventing HECTD4-mediated ubiquitination of IGF2BP3, thereby sustaining IGF2BP3 oncogenic activity in glioma.\",\n      \"method\": \"RNA pull-down, mass spectrometry, RIP, luciferase reporter, co-immunoprecipitation assays, in vitro/in vivo functional assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and mass spectrometry, single lab\",\n      \"pmids\": [\"35031058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF2BP3 promotes melanoma invasion and metastasis through a miR-7-independent mechanism downstream of CDR1as/LINC00632 silencing.\",\n      \"method\": \"Loss-of-function (CDR1as depletion), invasion assays in vitro, metastasis assays in vivo, epistasis experiments placing IGF2BP3 downstream of CDR1as\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with in vitro and in vivo validation, published in high-impact journal with strong evidence\",\n      \"pmids\": [\"31935372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF2BP3 directly binds the 3'UTR of oncogenic transcripts MYC and CDK6 to regulate their expression post-transcriptionally, promoting hematopoietic progenitor proliferation and survival in MLL-rearranged B-ALL.\",\n      \"method\": \"CLIP-seq (cross-link immunoprecipitation and high-throughput sequencing), knockdown leading to decreased proliferation/apoptosis, enforced expression in murine BM cells with phenotypic readout\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CLIP-seq with in vitro and in vivo validation, strong mechanistic follow-up\",\n      \"pmids\": [\"26974154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF2BP3 (IMP3) associates with a specific subset of circRNAs to form circRNA-protein complexes (circRNPs) of distinct sizes in mammalian cells, as identified by glycerol gradient centrifugation and RNA-seq of IMP3-co-immunoprecipitated RNA.\",\n      \"method\": \"Glycerol gradient centrifugation, RNA-seq of IMP3-coIP RNA, filtering for circular-junction reads, validation experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation plus RNA-seq, single lab\",\n      \"pmids\": [\"27510448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA DMDRMR binds IGF2BP3 and specifically enhances its m6A-dependent stabilization activity on target mRNAs including CDK4, COL6A1, LAMA5, and FN1 in clear cell renal cell carcinoma, enhancing G1-S transition.\",\n      \"method\": \"RNA pulldown, RIP, m6A-dependent mRNA stability assays, functional cell cycle assays, in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and functional methods, single lab\",\n      \"pmids\": [\"33293428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGF2BP3 (IMP3) forms cytoplasmic granules (RNP 'safe houses') that contain HMGA2 mRNA and other let-7 target mRNAs, protecting them from let-7-directed mRNA decay by sequestering them away from AGO1-4 and miRNAs.\",\n      \"method\": \"Cytoplasmic granule characterization, antagomiR experiments, removal of let-7 target sites, immunoprecipitation, global gene set enrichment analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across multiple targets, replicated concept in developing limb bud\",\n      \"pmids\": [\"24703842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGF2BP3 overexpression through THADA gene fusion leads to increased IGF2 translation and IGF1R signaling via PI3K and MAPK cascades, promoting cell proliferation, invasion, and transformation in thyroid cancer.\",\n      \"method\": \"Whole-transcriptome and whole-genome analysis, functional cell assays, in vitro and in vivo IGF1R inhibition rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genomic identification plus functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"28193878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF2BP3 destabilizes EIF4E-BP2 and MEIS3 mRNAs and interacts with ribonucleases XRN2 and exosome components, thereby promoting eIF4E-mediated translational activation and cancer cell proliferation.\",\n      \"method\": \"RNA-seq of IGF2BP3-depleted cells, immunoprecipitation-seq, co-immunoprecipitation with ribonucleases, rescue experiments with EIF4E-BP2 depletion, measurement of phospho-eIF4E\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro biochemical assays combined with rescue epistasis and sequencing, single lab but multiple methods\",\n      \"pmids\": [\"26522719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IMP2 and IMP3 cooperate to destabilize progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT transcription complex (CNOT1), thereby suppressing miR-200a transcription and promoting triple-negative breast cancer metastasis.\",\n      \"method\": \"Knockdown of IMP2/IMP3 with synergistic invasion/invadopodia readout, mRNA stability assays, co-immunoprecipitation with CNOT1 complex\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional validation, single lab\",\n      \"pmids\": [\"29217458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lin28b directly interacts with IGF2BP3, and their co-expression in adult hematopoietic stem and progenitor cells jointly stabilizes thousands of mRNAs (including Pax5 and Arid3a) by binding at the same sites, with IGF2BP3 mRNA itself forming an autoregulatory loop.\",\n      \"method\": \"Proteomics, in situ analyses, single-cell RNA-seq, enforced co-expression in adult HSPCs with in vivo fetal B-cell development readout\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus in situ interaction plus in vivo functional validation across multiple mRNA targets\",\n      \"pmids\": [\"31221665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF2BP3 regulates a posttranscriptional operon in MLL-Af4 leukemia that includes HOXA locus genes and Ras pathway transcripts, controlling both steady-state mRNA levels and pre-mRNA splicing, and is required for leukemia-initiating cell function.\",\n      \"method\": \"Igf2bp3 deletion in MLL-Af4 mouse leukemia model, survival analysis, CLIP-seq, splicing analysis, leukemia-initiating cell transplantation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic deletion with survival endpoint plus CLIP-seq mechanistic studies\",\n      \"pmids\": [\"34321607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal structure of IMP3 RRM12 shows that only RRM1 is involved in RNA binding and recognizes a dinucleotide sequence; the spatial orientation of RRM1 to RRM2 is unique compared to other tandem RRM structures.\",\n      \"method\": \"X-ray crystallography of IMP3 RRM12 and its complex with RNA, biochemical characterization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biochemical validation\",\n      \"pmids\": [\"30135093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IMP-3 and its protein partners ILF3/NF90 and PTBP1 bind to the 3'UTRs of cyclin D1 and D3 mRNAs, protecting them from miRNA-dependent translational repression mediated by AGO2/GW182 recruitment, in a nuclear localization-dependent manner.\",\n      \"method\": \"IMP-3 knockdown with rapid cyclin protein decrease while mRNAs remain polyribosome-associated, co-IP demonstrating IMP-3/ILF3/PTBP1 complex at 3'UTRs, epistasis with AGO2/GW182\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical co-IP plus functional rescue, single lab\",\n      \"pmids\": [\"27840950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGF2BP3 binds to CD44 mRNA and enhances CD44 expression in fibroblasts, which in turn increases IGF2 levels and stimulates breast cancer cell proliferation and drug resistance via Hedgehog signaling pathway.\",\n      \"method\": \"RNA-IP, co-culture of CD44+ fibroblasts with breast cancer cells, IGF2BP3 knockdown/overexpression, functional proliferation and drug resistance assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RIP plus functional assays, single lab\",\n      \"pmids\": [\"28523716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGF2BP3 directly associates with the deubiquitinase USP10 and attenuates its ability to stabilize p53, reducing p53 protein half-life and levels, leading to enhanced cell proliferation in lung cancer.\",\n      \"method\": \"Co-immunoprecipitation, half-life/pulse-chase assays of p53, IGF2BP3 overexpression/knockdown with p53 protein level readout, cell cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional mRNA stability and cell cycle assays, single lab\",\n      \"pmids\": [\"29212181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Zebrafish Igf2bp3 maintains maternal mRNA stability prior to maternal-to-zygotic transition; its depletion destabilizes maternal mRNAs and causes abnormal cytoskeleton organization and cell division, while overexpression stabilizes target mRNAs.\",\n      \"method\": \"Maternal igf2bp3 mutant zebrafish, mRNA stability assays, gene ontology analysis of Igf2bp3-bound mRNAs, phenotypic analysis of cytoskeleton and cell division\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant with multiple phenotypic readouts plus gain-of-function; strong evidence for mRNA stabilization function\",\n      \"pmids\": [\"32127635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 recognizes m6A-modified mRNAs encoding anti-ferroptotic factors (GPX4, SLC3A2, ACSL3, FTH1) through its m6A reading domain to stabilize them, thereby desensitizing lung adenocarcinoma cells to ferroptosis.\",\n      \"method\": \"IGF2BP3 overexpression/knockdown with mRNA stability measurement, m6A reading domain mutant analysis, functional ferroptosis assays, correlation in clinical samples\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis plus functional ferroptosis assays and clinical correlation, single lab\",\n      \"pmids\": [\"36457846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 interacts with RCC2 mRNA and stabilizes m6A-modified RCC2 mRNA in AML cells, sustaining AML cell survival and proliferation.\",\n      \"method\": \"IGF2BP3 knockdown in AML cells with RCC2 mRNA stability assay, RIP, in vitro and in vivo leukemia functional assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP with mRNA stability assays and in vivo validation, single lab\",\n      \"pmids\": [\"35217832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactylation of IGF2BP3 at lysine residues is required for it to capture PCK2 and NRF2 mRNAs; this lactylation also increases m6A methylation of PCK2 and NRF2 mRNAs, creating a feedback loop (lactylated IGF2BP3-PCK2-SAM-m6A) that promotes lenvatinib resistance in HCC.\",\n      \"method\": \"Lenvatinib-resistant cell models, lysine lactylation detection, RIP of PCK2/NRF2 mRNAs, metabolomics, mRNA stability assays, in vivo liposome siRNA delivery\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel PTM (lactylation) with mechanistic follow-up on mRNA targets and metabolic consequences, single lab\",\n      \"pmids\": [\"39450426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 preferentially binds internal mRNA m7G modifications (via its KH domains) and promotes degradation of m7G-modified transcripts, including TP53 (p53 mRNA) in cancer cells; this is mechanistically distinct from its m6A-stabilizing role (IGF2BP1 prefers m6A for stabilization).\",\n      \"method\": \"In vitro binding assays for m7G vs m6A preference, mRNA stability assays, site-specific m7G targeting with dCas13b system, IGF2BP3 modulation in glioblastoma with cancer progression readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assays plus dCas13b-guided site-specific validation plus cancer phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"39198433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 binds to the 3'UTR of COX6B2 mRNA in an m6A-dependent manner to increase its stability, elevating oxidative phosphorylation and driving acquired EGFR-TKI resistance in non-small cell lung cancer.\",\n      \"method\": \"RIP, mRNA stability assays, m6A-dependent COX6B2 binding, IGF2BP3 overexpression/knockdown with OXPHOS measurement, patient-derived xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with in vivo PDX validation and mechanistic pathway (m6A-dependent 3'UTR binding → OXPHOS → resistance)\",\n      \"pmids\": [\"37061993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 stabilizes MCM5 mRNA in an m6A-dependent manner; MCM5 protein then competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizing NICD1 and inducing partial EMT and lung adenocarcinoma metastasis.\",\n      \"method\": \"MeRIP-seq, RIP, mRNA stability assays, epistasis experiments (MCM5 overexpression, NICD1 acetylation assays), functional EMT/metastasis readouts in vitro and in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods plus in vivo validation, single lab\",\n      \"pmids\": [\"37171793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF2BP3 directly binds and stabilizes HIF1A mRNA at a specific m6A site in its coding region in gastric cancer cells, thereby promoting hypoxia-induced cell migration and angiogenesis.\",\n      \"method\": \"RIP, luciferase reporter assay, mRNA stability assay, IGF2BP3 knockdown with HIF1A overexpression rescue, Transwell and CAM angiogenesis assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP with luciferase reporter validation and functional rescue, single lab\",\n      \"pmids\": [\"34621671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates and stabilizes IGF2BP3 protein, protecting it from proteasomal degradation, thereby promoting colorectal cancer proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, IGF2BP3 protein half-life analysis, rescue experiments with IGF2BP3 overexpression after USP11 knockdown\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay plus functional rescue, single lab\",\n      \"pmids\": [\"33594305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Parkin (PARK2) directly ubiquitinates IGF2BP3 at K213 (in the first KH domain) and promotes its proteasomal degradation; this ubiquitination site is required for IGF2BP3's m6A reader function and its activation of PI3K/MAPK signaling in cervical cancer.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry for ubiquitination site identification (K213), in vivo/in vitro ubiquitination assays, KH domain mutant loss-of-function, xenograft model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry site identification plus mutagenesis plus functional validation in vitro and in vivo\",\n      \"pmids\": [\"37877353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circNFATC3 binds IGF2BP3 in the cytoplasm and prevents TRIM25-mediated ubiquitination of IGF2BP3, stabilizing IGF2BP3 protein which then enhances CCND1 mRNA stability in gastric cancer.\",\n      \"method\": \"RIP-seq to identify circRNAs bound to IGF2BP3, RIP, RNA-FISH/IF, IP, ubiquitination assays, TRIM25 knockdown rescue experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP-seq, co-IP, ubiquitination), single lab\",\n      \"pmids\": [\"37340423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circRARS binds to the KH1-KH2 domains of IGF2BP3 (via a 12-nt sequence GUCUUCCAGCAA) to enhance IGF2BP3's m6A recognition activity; the IGF2BP3/circRARS complex stabilizes target mRNAs (CAPN15, CD44, HMGA2, TNRC6A, ZMIZ2) through recruitment of stabilizer proteins HuR, Matrin3, and pAbPC1.\",\n      \"method\": \"Meta-analysis, IGF2BP3 domain binding mapping, RNA pulldown with 12-nt sequence validation, RIP, identification of stabilizer protein complex\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping plus RIP plus complex characterization, single lab\",\n      \"pmids\": [\"38073586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 binds and stabilizes MMP3 mRNA through interaction with N6-methyladenosine modification, promoting cardiomyocyte proliferation and cardiac regeneration after myocardial infarction in mice.\",\n      \"method\": \"Gain- and loss-of-function in vitro and in vivo (mouse MI model), RIP, m6A-dependent mRNA stability assay for MMP3, cardiomyocyte proliferation quantification\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP with mRNA stability plus in vivo cardiac regeneration model, single lab\",\n      \"pmids\": [\"37188676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 binds to and destabilizes m6A-methylated SLIT2 mRNA, impairing SLIT2/ROBO1 downstream signaling and activating PI3K/AKT and MEK/ERK pathways to promote triple-negative breast cancer metastasis.\",\n      \"method\": \"RIP, m6A site mapping, mRNA stability assay for SLIT2, IGF2BP3 KD with SLIT2/ROBO1 signaling readout, in vivo metastasis model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP with mRNA stability and signaling assays plus in vivo validation, single lab\",\n      \"pmids\": [\"36250924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 upregulates MIB1 (E3 ubiquitin ligase) expression, promoting FTO degradation via the ubiquitin-proteasome pathway, resulting in increased m6A-mediated CSF3 release and neutrophil extracellular trap (NET) formation in glioma.\",\n      \"method\": \"IGF2BP3 overexpression/knockdown, ubiquitin-proteasome pathway analysis for FTO degradation, m6A sequencing for CSF3, NET formation assays, BET inhibitor combination in vivo models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical readouts with in vivo glioma models, single lab\",\n      \"pmids\": [\"38167409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGF2BP3 promotes trophoblast cell invasion and migration in early human placenta; it is highly expressed in cytotrophoblast cells and its loss correlates with reduced trophoblast invasiveness and pre-eclampsia.\",\n      \"method\": \"In vitro cell invasion/migration assays, ex vivo explant culture model, expression analysis comparing first vs. third trimester and pre-eclamptic vs. normal placentas\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and ex vivo functional assays with clear phenotypic readout, single lab\",\n      \"pmids\": [\"24457969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IMP3 promotes prostate cancer progression by increasing SMURF1 expression, which then facilitates PTEN ubiquitination and activates the PI3K/AKT/mTOR signaling pathway.\",\n      \"method\": \"Immunoprecipitation/ubiquitination assay of PTEN, SMURF1 overexpression/knockdown rescue experiments, Western blotting of PI3K/AKT/mTOR pathway components\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP/ubiquitination assays with functional rescue experiments, single lab\",\n      \"pmids\": [\"32938489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 recognizes m6A-modified mRNAs of serine synthesis pathway genes (ATF4, PHGDH, PSAT1) to stabilize them, sustaining serine biosynthesis in AML cells and leukemia stem/initiating cells; this represents a metabolic vulnerability targetable by dietary serine restriction.\",\n      \"method\": \"CRISPR/Cas9 screen, RIP/m6A assays for SSP gene mRNAs, mRNA stability assays, in vitro and in vivo AML models with serine/glycine deprivation, normal hematopoiesis controls\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR screen plus RIP/m6A validation plus in vivo metabolic intervention, multiple orthogonal approaches\",\n      \"pmids\": [\"40328743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 deficiency reduces m6A content in Jagged1 (Jag1) mRNA, reducing Notch/Hes1 signaling and GPX4 expression, thereby promoting hepatic stellate cell ferroptosis and reducing liver fibrosis.\",\n      \"method\": \"HSC-specific IGF2BP3 knockout, multi-omics analysis, m6A measurement of Jag1, Hes1 and GPX4 mRNA/protein quantification, ferroptosis functional assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with multi-omics and functional ferroptosis assays, single lab\",\n      \"pmids\": [\"39113232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP-mediated m6A modification of ULK1 mRNA is recognized and stabilized by IGF2BP3, elevating ULK1 expression and enhancing protective mitophagy in epithelial ovarian cancer.\",\n      \"method\": \"m6A target identification, RIP, mRNA stability assay for ULK1, WTAP/IGF2BP3 knockdown with ULK1 and mitophagy readouts, in vitro/in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus mRNA stability with functional mitophagy readout, single lab\",\n      \"pmids\": [\"38286802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15-mediated m6A modification of VEGFA mRNA is stabilized by IGF2BP3 (and YTHDF2), leading to enhanced VEGFA expression and angiogenesis (HUVEC migration and tube formation) in hepatocellular carcinoma.\",\n      \"method\": \"MeRIP-seq, RIP, CLIP-seq integration, RBM15/IGF2BP3/YTHDF2 knockdown with VEGFA mRNA stability and angiogenesis readouts, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics integration plus functional angiogenesis validation, single lab\",\n      \"pmids\": [\"39092767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 binds the 3'UTR of HMGB1 mRNA to enhance its stability and promote HMGB1 expression, sustaining inflammation and bladder cancer progression; this relationship between HMGB1 mRNA and IGF2BP3 is conserved in mammalian embryonic development.\",\n      \"method\": \"RIP, mRNA stability assays, IGF2BP3 knockdown/overexpression with HMGB1 protein/mRNA readout, xenograft model, pharmacological HMGB1 inhibition rescue\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP with mRNA stability and functional rescue, single lab\",\n      \"pmids\": [\"38504159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 interacts with MYLK mRNA in an m6A-dependent manner, extending its half-life and inhibiting ERK1/2 phosphorylation, thereby suppressing MSC adipogenesis; IGF2BP3 overexpression in adipose tissue reduces body weight and improves insulin resistance in HFD mice.\",\n      \"method\": \"RIP, m6A-dependent mRNA stability for MYLK, IGF2BP3 overexpression/knockdown in MSC adipogenesis model, adeno-associated virus adipose-specific overexpression with metabolic readouts in HFD mice\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP/m6A assays with in vivo metabolic phenotype, single lab\",\n      \"pmids\": [\"38196046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NONO synergizes with IGF2BP3 to promote exon 6 skipping in DLG1 in an m6A-dependent manner in gallbladder cancer; IGF2BP3 disrupts the binding of RBM14 to NONO, relieving RBM14-mediated inhibition of NONO-driven alternative splicing.\",\n      \"method\": \"mRNA-seq, RIP-seq, Co-IP/mass spectrometry identifying IGF2BP3-NONO-RBM14 complex, m6A manipulation, percent-spliced-in (PSI) analysis, functional YAP1/JUN pathway readouts\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS plus RNA-seq and m6A manipulation with functional splice isoform validation, single lab\",\n      \"pmids\": [\"38341127\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2BP3 is a multifunctional RNA-binding protein that primarily acts as an m6A reader (through its KH domains, with RRM1 also mediating direct RNA contact as shown by crystal structure) to stabilize target mRNAs post-transcriptionally, but can also promote mRNA degradation of m7G-modified transcripts; it forms cytoplasmic RNP 'safe houses' that protect oncogenic mRNAs (e.g., HMGA2, MYC, CDK6) from miRNA/AGO2-directed decay, stabilizes serine synthesis pathway and other oncogenic transcripts to fuel cancer metabolic reprogramming, is regulated by ubiquitination (Parkin at K213, TRIM25, TRIM21, USP11 deubiquitinase) and lactylation (which modulates its mRNA-binding specificity), and is amplified in activity by circRNAs (e.g., circNEIL3, circRARS) that prevent its ubiquitination or enhance its m6A recognition, collectively driving proliferation, invasion, metastasis, immune evasion, and drug resistance across multiple cancer types while also playing physiological roles in trophoblast invasion, hematopoietic development, cardiomyocyte regeneration, and maternal mRNA stability.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"IGF2BP3 (IMP3) was identified as a member of a family of three IGF-II mRNA-binding proteins (IMPs) that bind the 5' UTR of translationally regulated IGF-II leader 3 mRNA but not the constitutively translated leader 4 mRNA, causing dose-dependent translational repression of IGF-II leader 3 mRNA. The proteins contain two RNA recognition motifs and four KH domains and localize to subcytoplasmic domains in a growth-dependent and cell-specific manner.\",\n      \"method\": \"RNA binding assays, luciferase reporter translational repression assay, immunolocalization, developmental expression analysis in mouse and human embryos\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original biochemical characterization with multiple orthogonal methods; foundational paper with >600 citations\",\n      \"pmids\": [\"9891060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGF2BP1/2/3 function as a distinct family of m6A readers that recognize the consensus GG(m6A)C sequence on thousands of mRNA transcripts, promoting mRNA stability and storage (e.g., MYC mRNA) in an m6A-dependent manner under normal and stress conditions, in contrast to the decay-promoting YTHDF2 reader. The K homology (KH) domains of IGF2BPs are required for m6A recognition and are critical for their oncogenic functions.\",\n      \"method\": \"m6A-seq, PAR-CLIP, RIP, RNA stability assays, mutagenesis of KH domains, in vitro binding assays, functional cancer cell assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, replicated across paralogs, >2300 citations; foundational m6A reader paper\",\n      \"pmids\": [\"29476152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of IMP3 RRM12 (N-terminal tandem RNA recognition motifs) bound to short RNA sequences revealed that both RRM domains adopt canonical RRM topology with a unique spatial orientation relative to each other compared to other tandem RRM structures. Only RRM1 is directly involved in RNA binding and recognizes a dinucleotide sequence.\",\n      \"method\": \"X-ray crystallography, biochemical RNA-binding characterization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional biochemical validation\",\n      \"pmids\": [\"30135093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IMP3 (IGF2BP3) RNPs function as cytoplasmic 'safe houses' that protect oncogenic let-7 target mRNAs (including HMGA2 and LIN28B) from miRNA-directed mRNA decay. IMP3-containing granules are depleted of Ago1-4 and miRNAs, IMP3 dose-dependently increases HMGA2 mRNA levels, and let-7 antagomiRs render HMGA2 refractory to IMP3 stabilization. Removal of let-7 target sites eliminates IMP3-dependent stabilization.\",\n      \"method\": \"Transcriptome analysis of cancer data, cytoplasmic granule fractionation, RIP, let-7 antagomiR experiments, deletion of 3'UTR let-7 binding sites, IMP1-deficient mouse embryo analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic (let-7 site deletion, IMP1-KO embryos) and biochemical (RIP, fractionation)\",\n      \"pmids\": [\"24703842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF2BP3 (IMP3) is specifically overexpressed in MLL-rearranged B-ALL and is required for survival of B-ALL cell lines (knockdown causes decreased proliferation and increased apoptosis). CLIP-seq identified oncogenes MYC and CDK6 as direct IGF2BP3 targets regulated via 3'UTR binding elements. Enforced IGF2BP3 expression in murine BM cells enhanced Myc and Cdk6 expression, promoted hematopoietic stem/progenitor cell proliferation, and skewed development to B cell/myeloid lineage.\",\n      \"method\": \"CLIP-seq, knockdown/overexpression in cell lines and mouse BM transplant, 3'UTR reporter assays, mRNA expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CLIP-seq identification of direct targets combined with in vivo mouse model and functional validation\",\n      \"pmids\": [\"26974154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IMP3 (IGF2BP3) associates with circRNAs to form circRNA-protein complexes (circRNPs) of distinct sizes in mammalian cells. A specific set of IMP3-associated circRNAs was identified by combining RNA-seq of IMP3-co-immunoprecipitated RNA with filtering for circular-junction reads, defining a subfamily of circRNPs.\",\n      \"method\": \"Glycerol gradient centrifugation, polysome gradient fractionation, RNA-seq of immunoprecipitated RNA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation plus RNA-seq, single lab, novel finding\",\n      \"pmids\": [\"27510448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IMP-3 (IGF2BP3) and its protein partners ILF3/NF90 and PTBP1 bind to the 3'UTRs of cyclin D1 and D3 mRNAs and protect them from translational repression induced by miRNA-dependent recruitment of the AGO2/GW182 complex. Knockdown of IMP-3 causes rapid decrease in cyclin protein levels while their mRNAs remain stable and polysome-associated but untranslated.\",\n      \"method\": \"RIP, polysome fractionation, knockdown experiments, protein level analysis\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single lab; mechanistic dissection of translational protection\",\n      \"pmids\": [\"27840950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF2BP3 destabilizes EIF4E-BP2 and MEIS3 mRNAs by interacting with ribonucleases XRN2 and exosome components (co-immunoprecipitation), thereby facilitating eIF4E-mediated translational activation. Depletion of EIF4E-BP2 partially rescues the growth retardation caused by IGF2BP3 knockdown, and IGF2BP3 depletion reduces phosphorylated (active) eIF4E. This was the first demonstration of IGF2BP3 as an RNA-destabilizing factor.\",\n      \"method\": \"RNA-seq, RIP-seq, co-immunoprecipitation with ribonucleases, mRNA stability assays, rescue experiments, analysis of human lung adenocarcinoma tissues\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; genetic epistasis rescue; clinical tissue correlation\",\n      \"pmids\": [\"26522719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"THADA gene fusion to LOC389473 (located 12 kb upstream of IGF2BP3) does not produce a chimeric protein but instead drives strong overexpression of full-length IGF2BP3 mRNA and protein in thyroid cancer, leading to increased IGF2 translation, activation of IGF1R/PI3K and MAPK signaling, and promotion of cell proliferation, invasion, and transformation. Inhibition of IGF1R blocks growth of IGF2BP3-overexpressing cells and tumors in vitro and in vivo.\",\n      \"method\": \"Whole-transcriptome and whole-genome sequencing, functional cell assays, IGF1R inhibitor treatment, in vivo xenograft\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genomic and functional validation, in vitro and in vivo evidence, mechanistic pathway identification\",\n      \"pmids\": [\"28193878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IMP2 and IMP3 (IGF2BP2/3) are specifically overexpressed in triple-negative breast cancer, directly target progesterone receptor (PR) mRNA for destabilization through recruitment of the CCR4-NOT (CNOT1) complex, thereby suppressing transcription of miR-200a (which normally targets IMP2/3), forming a double-negative feedback loop that promotes EMT and metastasis.\",\n      \"method\": \"Knockdown/overexpression, cell invasion/invadopodia assays, mRNA stability assays, identification of CNOT1 complex recruitment, luciferase 3'UTR reporter, miRNA functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods; molecular mechanism dissected; single lab study\",\n      \"pmids\": [\"29217458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGF2BP3 directly associates with the deubiquitinase USP10 and attenuates its ability to stabilize p53 protein, promoting lung tumorigenesis. IGF2BP3 silencing increases p53 half-life and protein level and induces G0/G1 cell cycle arrest.\",\n      \"method\": \"Co-immunoprecipitation, protein half-life assays (cycloheximide chase), knockdown/overexpression, flow cytometry cell cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and functional rescue; single lab\",\n      \"pmids\": [\"29212181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lin28b directly interacts with Igf2bp3 (proteomics and in situ analyses), and their co-expression in adult HSPCs reactivates fetal-like B-cell development more efficiently than either factor alone. In B-cell progenitors, Lin28b and Igf2bp3 jointly stabilize thousands of mRNAs (including Pax5 and Arid3a) by binding at the same sites, and Igf2bp3 mRNA itself is stabilized in an autoregulatory loop.\",\n      \"method\": \"Single-cell RNA-seq, proteomics, in situ analysis, CLIP/RIP-seq, in vivo mouse hematopoietic transplantation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomics + in vivo functional validation + transcriptome-wide binding data; multiple orthogonal approaches\",\n      \"pmids\": [\"31221665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Igf2bp3 is an essential regulator of maternal mRNA stability in zebrafish. Depletion of maternal igf2bp3 destabilizes maternal mRNAs prior to maternal-to-zygotic transition and causes severe developmental defects including abnormal cytoskeleton organization and cell division, while oogenesis and maternal mRNA levels in unfertilized eggs are normal. Igf2bp3 overexpression enhances stability of its target maternal mRNAs, and depletion or excess Igf2bp3 both impair embryogenesis.\",\n      \"method\": \"Maternal-specific mutant zebrafish, RNA-seq, Gene ontology analysis, mRNA stability assays, gain- and loss-of-function\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function (maternal mutant) plus gain-of-function with transcriptome-wide characterization in a vertebrate model\",\n      \"pmids\": [\"32127635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DMDRMR (a lncRNA) binds IGF2BP3 to enhance its m6A-dependent activity on specific target mRNAs including CDK4, COL6A1, LAMA5, and FN1, stabilizing these transcripts and promoting G1-S transition and cell proliferation in clear cell renal cell carcinoma.\",\n      \"method\": \"RIP, RNA pulldown, m6A-seq, mRNA stability assays, functional cell and in vivo tumor assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + m6A-seq + functional validation; single lab study\",\n      \"pmids\": [\"33293428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF2BP3 is critical for MLL-Af4-mediated leukemogenesis; deletion of Igf2bp3 significantly increases survival of mice with MLL-Af4-driven leukemia with minimal impact on baseline hematopoiesis. IGF2BP3 regulates a posttranscriptional operon including Hoxa locus genes and Ras pathway genes, controlling both steady-state mRNA levels and pre-mRNA splicing.\",\n      \"method\": \"Conditional genetic deletion in mouse leukemia model, survival analysis, leukemia-initiating cell functional assays, RNA-seq, CLIP-seq\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion in in vivo leukemia model with genome-wide RNA-seq/CLIP-seq; clean causal evidence\",\n      \"pmids\": [\"34321607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"circNDUFB2 acts as a scaffold to enhance the interaction between E3 ubiquitin ligase TRIM25 and IGF2BPs (including IGF2BP3), forming a TRIM25/circNDUFB2/IGF2BPs ternary complex that facilitates ubiquitination and proteasomal degradation of IGF2BPs; this effect is enhanced by m6A modification of circNDUFB2.\",\n      \"method\": \"RIP, RNA pulldown, co-immunoprecipitation, ubiquitination assays, m6A modification analysis, in vitro and in vivo functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods establishing the ternary complex and ubiquitination mechanism\",\n      \"pmids\": [\"33436560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A modification of PD-L1 mRNA is recognized by IGF2BP3, which stabilizes PD-L1 mRNA in breast cancer cells, promoting tumor immune escape. METTL3 knockdown abolishes m6A modification and reduces PD-L1 mRNA stabilization; IGF2BP3 knockdown or METTL3 inhibition enhances anti-tumor T cell activity both in vitro and in vivo.\",\n      \"method\": \"MeRIP-seq, epitranscriptomic microarray, MeRIP-qPCR, RIP-qPCR, mouse xenograft models, tissue microarray\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP-seq + RIP-qPCR + in vivo validation; multiple methods establishing the METTL3/m6A/IGF2BP3/PD-L1 axis\",\n      \"pmids\": [\"35197058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The m6A reader IGF2BP3 enhances stability of m6A-modified RCC2 mRNA in an m6A-dependent manner in acute myeloid leukemia cells. IGF2BP3 knockdown dramatically suppresses AML cell survival, reduces proliferation, impairs apoptosis resistance, and attenuates leukemic capacity in vitro and in vivo.\",\n      \"method\": \"RIP, mRNA stability assays, m6A-dependent binding assays, knockdown/overexpression, in vivo mouse AML model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + stability assays + in vivo model; single lab\",\n      \"pmids\": [\"35217832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IMP3 (IGF2BP3) promotes prostate cancer metastasis by physically binding HDAC4 mRNA and enhancing its stability, thereby activating ERK signaling and inducing EMT. This is one of two parallel axes by which hsa_circ_0003258 promotes metastasis, the other being miR-653-5p sponging.\",\n      \"method\": \"RNA pulldown, RIP, Western blot, rescue experiments, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RIP/pulldown with functional rescue; single lab\",\n      \"pmids\": [\"34986849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 desensitizes lung adenocarcinoma cells to ferroptosis in an m6A reading domain-dependent manner by binding m6A-methylated mRNAs encoding anti-ferroptotic factors (GPX4, SLC3A2, ACSL3, FTH1), stabilizing these transcripts and sustaining anti-ferroptotic protein levels.\",\n      \"method\": \"m6A reader domain mutagenesis, RIP, mRNA stability assays, ferroptosis markers measurement, clinical specimen correlation\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis + RIP + stability assays; single lab\",\n      \"pmids\": [\"36457846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circNEIL3 stabilizes IGF2BP3 protein by preventing HECTD4-mediated ubiquitination of IGF2BP3, thereby protecting its oncogenic function in glioma. Additionally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and delivered to tumor-associated macrophages where it similarly stabilizes IGF2BP3 to promote immunosuppressive polarization.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RIP, luciferase reporter, co-immunoprecipitation, ubiquitination assays, exosome characterization\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods; identifies HECTD4 as ubiquitin ligase for IGF2BP3\",\n      \"pmids\": [\"35031058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM25 E3 ubiquitin ligase promotes ubiquitination and degradation of IGF2BP3, and this process is competitively inhibited by circNFATC3 which binds IGF2BP3 in the cytoplasm, preventing TRIM25-mediated ubiquitination and thereby enhancing IGF2BP3 stability and its regulatory activity on CCND1 mRNA in gastric cancer.\",\n      \"method\": \"RIP, RNA-FISH/IF, co-immunoprecipitation, ubiquitin assays, rescue experiments, in vivo tumor model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods; identifies TRIM25 as E3 ligase for IGF2BP3\",\n      \"pmids\": [\"37340423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 recognizes m6A-modified minichromosome maintenance complex component MCM5 mRNAs to stabilize them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizing NICD1 and overactivating Notch signaling to induce partial EMT in lung adenocarcinoma.\",\n      \"method\": \"RIP, MeRIP-seq, mRNA stability assays, co-immunoprecipitation, SIRT1 deacetylation assays, functional EMT assays, clinical specimen analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods across the IGF2BP3/MCM5/SIRT1/NICD1 axis; single lab\",\n      \"pmids\": [\"37171793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 stabilizes COX6B2 mRNA by binding to its 3'-UTR in an m6A-dependent manner, increasing oxidative phosphorylation (OXPHOS) activity, and thereby driving acquired resistance to EGFR tyrosine kinase inhibitors. The IGF2BP3-COX6B2 axis also regulates nicotinamide metabolism to further alter OXPHOS and promote resistance.\",\n      \"method\": \"RIP, MeRIP analysis, mRNA stability assays, OXPHOS metabolic assays, siRNA knockdown, patient-derived xenograft model, OXPHOS inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP + mRNA stability + metabolic assays + PDX model; multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"37061993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circRARS binds to the KH1-KH2 domains of IGF2BP3 (via a 12-nt sequence GUCUUCCAGCAA) to enhance IGF2BP3's m6A modification recognition activity, and the IGF2BP3/circRARS complex recruits stabilizer proteins HuR, Matrin3, and pAbPC1 to increase mRNA stability of target genes (CAPN15, CD44, HMGA2, TNRC6A, ZMIZ2) in an m6A-dependent manner.\",\n      \"method\": \"RIP, RNA pulldown, domain mapping, m6A binding assays, functional in vitro and in vivo assays, identification of specific binding sequence\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-level binding specificity mapped plus m6A-dependent functional validation; single lab\",\n      \"pmids\": [\"38073586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Parkin E3 ubiquitin ligase directly interacts with IGF2BP3 and promotes its proteasomal degradation by ubiquitinating it; the ubiquitination site was mapped to K213 in the first KH domain of IGF2BP3. IGF2BP3 K213 mutation abolishes its oncogenic m6A reader function and inactivates PI3K and MAPK signaling in cervical cancer.\",\n      \"method\": \"Co-immunoprecipitation, in vivo and in vitro ubiquitination assays, mass spectrometry ubiquitination site mapping, RNA-IP, xenograft mouse model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination site precisely mapped by mass spectrometry, functional consequence of site mutation validated; multiple orthogonal methods\",\n      \"pmids\": [\"37877353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP11 deubiquitinase directly interacts with IGF2BP3 and protects it from proteasomal degradation via deubiquitination, as demonstrated by co-immunoprecipitation and ubiquitination assays. IGF2BP3 overexpression reverses the decrease in colorectal cancer cell proliferation, migration, and invasion caused by USP11 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Western blotting, rescue experiments, in vivo tumor assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and ubiquitination assays with functional rescue; single lab\",\n      \"pmids\": [\"33594305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 promotes mRNA degradation through binding internal m7G-modified mRNAs. IGF2BP family proteins preferentially bind internal mRNA m7G, but with distinct functional consequences: IGF2BP3 binding promotes degradation of m7G target transcripts (including TP53 mRNA at its 3'UTR in glioblastoma), whereas IGF2BP1 prefers m6A to stabilize transcripts. Modulating IGF2BP3 or site-specific m7G targeting via dCas13b affects TP53 mRNA half-life, cancer progression, and chemosensitivity.\",\n      \"method\": \"m7G-modified RNA pull-down, binding assays, mRNA stability (half-life) assays, dCas13b site-specific targeting, functional cancer cell assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel mechanistic finding with in vitro binding, site-specific dCas13b functional validation, and in vivo relevance; multiple methods\",\n      \"pmids\": [\"39198433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 stabilizes EGFR mRNA in an m6A-dependent manner (cooperating with METTL14) and promotes EGFR pathway activation and cetuximab resistance in colorectal cancer.\",\n      \"method\": \"RIP, MeRIP, mRNA stability assays, functional cell and in vivo assays, clinical specimen analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + MeRIP + stability assays; single lab\",\n      \"pmids\": [\"37658049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 binds SLIT2 mRNA and destabilizes m6A-methylated SLIT2 mRNA, impairing SLIT2/ROBO1 signaling and consequently activating PI3K/AKT and MEK/ERK pathways to promote triple-negative breast cancer migration and invasion.\",\n      \"method\": \"RIP, mRNA stability assays, m6A modification analysis, functional migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + stability + m6A; single lab; demonstrates m6A-dependent destabilization (opposite polarity to canonical IGF2BP3 stabilization)\",\n      \"pmids\": [\"36250924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 promotes myocardial regeneration by binding and stabilizing MMP3 mRNA through m6A modification interaction. IGF2BP3 expression progressively decreases postnatally but is re-induced after cardiac injury. MMP3 acts as a downstream effector of IGF2BP3 to regulate cardiomyocyte proliferation, and IGF2BP3 promotes cardiac function recovery after myocardial infarction in mice.\",\n      \"method\": \"Gain- and loss-of-function in vitro and in vivo (mouse MI model), RIP, mRNA stability assays, m6A analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse cardiac model with RIP and stability assays; single lab\",\n      \"pmids\": [\"37188676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 synergizes with NONO to promote exon 6 skipping in DLG1 pre-mRNA in an m6A-dependent manner, and IGF2BP3 disrupts the binding of RBM14 to NONO, thereby relieving RBM14's inhibition of NONO-mediated alternative splicing in gallbladder cancer.\",\n      \"method\": \"RIP-seq, mRNA-seq, co-immunoprecipitation/mass spectrometry, alternative splicing analysis (PSI values), functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of splicing regulation by IP/MS and RIP-seq; single lab\",\n      \"pmids\": [\"38341127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In glioma, IGF2BP3 enhances expression of E3 ubiquitin ligase MIB1, promoting FTO (m6A demethylase) degradation via the ubiquitin-proteasome pathway, resulting in increased m6A-mediated CSF3 release and NET (neutrophil extracellular trap) formation, which impedes oncolytic virus replication.\",\n      \"method\": \"Functional assays, ubiquitin-proteasome pathway analysis, m6A analysis, in vivo mouse glioma models, BET inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic chain established in vitro and in vivo; single lab\",\n      \"pmids\": [\"38167409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactylation of IGF2BP3 (driven by increased glycolysis and lactate accumulation in lenvatinib-resistant HCC) is crucial for IGF2BP3 to capture PCK2 and NRF2 mRNAs and enhance their stability. The lactylated IGF2BP3 also increases SAM availability, fueling m6A methylation of PCK2 and NRF2 mRNAs, creating a positive feedback loop that reinforces drug resistance.\",\n      \"method\": \"Lactylation assays, RIP, MeRIP, mRNA stability assays, metabolomics, in vivo lenvatinib-resistant models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel PTM (lactylation) mechanistically linked to RNA binding function; multiple methods; single lab\",\n      \"pmids\": [\"39450426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 stabilizes HMGB1 mRNA by binding to it, promoting HMGB1 expression and bladder cancer progression; this relationship between HMGB1 mRNA and IGF2BP3 is also conserved in mammalian embryonic development where both genes decrease as development progresses. The IGF2BP3 gene is regulated by copy number gain/amplification, promoter hypomethylation, and miR-320a-3p.\",\n      \"method\": \"RIP, mRNA stability assays, bisulfite sequencing, luciferase reporter, xenograft mouse model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + stability assays + multiple regulatory mechanism analysis; single lab\",\n      \"pmids\": [\"38504159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP-mediated m6A modification of ULK1 mRNA enhances its stability in an IGF2BP3-dependent manner, leading to elevated ULK1 expression and enhanced mitophagy in epithelial ovarian cancer, contributing to disease progression.\",\n      \"method\": \"MeRIP, RIP, mRNA stability assays, functional mitophagy assays, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP + RIP + functional validation; single lab\",\n      \"pmids\": [\"38286802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 regulates SCD mRNA m6A modifications via an IGF2BP3-METTL14 complex, enhancing SCD mRNA stability to promote lipid metabolism, proliferation, and metastasis in cervical cancer.\",\n      \"method\": \"RNA-seq, RIP assay, MeRIP, lipid droplet/TG/fatty acid assays, in vivo nude mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + MeRIP + metabolic validation; single lab\",\n      \"pmids\": [\"38355626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1 mRNA 3'UTR is bound by IGF2BP3 in an m6A-dependent manner (MeRIP-qPCR and RIP-qPCR), enhancing SENP1 expression and stability in AML. IGF2BP3-stabilized SENP1 promotes AKT pathway activation via de-SUMOylation of HDAC2, which enhances EGFR transcription.\",\n      \"method\": \"CO-IP, MeRIP-qPCR, RIP-qPCR, RNA pulldown, SUMO assay, ChIP-qPCR, in vitro and in vivo AML models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays establishing the IGF2BP3/m6A/SENP1/HDAC2 axis; single lab\",\n      \"pmids\": [\"38822351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15 (m6A writer) mediates m6A modification of VEGFA mRNA, which is then recognized and stabilized by IGF2BP3, leading to enhanced VEGFA expression and HUVEC tube formation/migration. Knockdown of IGF2BP3 reduces VEGFA expression and inhibits tumor angiogenesis in HCC xenograft models.\",\n      \"method\": \"MeRIP-seq, RNA-seq, CLIP-seq, RIP, cell and molecular biology validation, HCC xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics plus functional validation; single lab\",\n      \"pmids\": [\"39092767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 binds MYLK mRNA in an m6A-dependent manner, extending its half-life and inhibiting ERK1/2 phosphorylation, thereby repressing MSC adipogenesis. IGF2BP3 overexpression in adipose tissue (via AAV) reduces body weight and improves insulin resistance in high-fat diet mice.\",\n      \"method\": \"RIP, mRNA stability assays, m6A-dependent binding validation, ERK signaling analysis, in vivo AAV delivery, metabolic phenotyping\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP + stability + in vivo AAV model; single lab; demonstrates physiological role in metabolism\",\n      \"pmids\": [\"38196046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 recognizes m6A on mRNAs of key serine synthesis pathway (SSP) genes (ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the metabolic demands of AML cells and leukemia stem/initiating cells. CRISPR/Cas9 screen identified that IGF2BP3 depletion sensitizes AML cells to serine/glycine deprivation; combined IGF2BP3 silencing with dietary SG restriction potently inhibits AML in vitro and in vivo while sparing normal hematopoiesis.\",\n      \"method\": \"CRISPR/Cas9 screen, RIP, mRNA stability assays, metabolomics, dietary restriction in vivo mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen + RIP + in vivo validation + metabolomics; multiple orthogonal approaches\",\n      \"pmids\": [\"40328743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGF2BP3 (IMP3) promotes trophoblast cell invasion and migration in placenta. IGF2BP3 is highly expressed in cytotrophoblast cells during early pregnancy and is reduced in the third trimester and in pre-eclamptic placentas. In vitro invasion/migration assays and ex vivo explant culture demonstrated that IGF2BP3 promotes trophoblast invasion.\",\n      \"method\": \"Immunohistochemistry in human placentas, in vitro invasion/migration assays, ex vivo explant culture model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional invasion assays in primary cells with clinical correlation; no defined molecular target in trophoblasts\",\n      \"pmids\": [\"24457969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In CD44-positive fibroblasts, IGF2BP3 binds CD44 mRNA and enhances its expression, which increases IGF2 secretion by fibroblasts, stimulating breast cancer cell proliferation and paclitaxel resistance via Hedgehog signaling activation in breast cancer cells.\",\n      \"method\": \"Co-culture experiments, RIP for IGF2BP3-CD44 mRNA interaction, functional proliferation/drug resistance assays, Hedgehog pathway analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RIP with functional co-culture assay; single lab; limited molecular mechanistic depth\",\n      \"pmids\": [\"28523716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IMP3 (IGF2BP3) accelerates prostate cancer progression by increasing SMURF1 expression, which facilitates PTEN ubiquitination and degradation, activating the PI3K/AKT/mTOR signaling pathway.\",\n      \"method\": \"Immunoprecipitation/ubiquitination assays, Western blotting for PI3K/AKT/mTOR pathway, knockdown/overexpression, rescue experiments with SMURF1 silencing\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assays + pathway rescue; single lab; mechanism identified\",\n      \"pmids\": [\"32938489\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2BP3 is an oncofetal RNA-binding protein containing two RRM domains (RRM1 mediates RNA binding) and four KH domains (required for m6A recognition) that functions primarily as an m6A reader to stabilize thousands of target mRNAs by recognizing the GG(m6A)C consensus sequence; it can also destabilize mRNAs through interaction with ribonucleases (e.g., XRN2, exosome) or by binding internal m7G-modified mRNAs; its activity and stability are regulated by multiple post-translational mechanisms including ubiquitination by HECTD4, TRIM25, and Parkin (at K213 in the KH1 domain), deubiquitination by USP11, and lysine lactylation; it directly targets oncogenic transcripts including MYC, CDK6, HMGA2, RCC2, EGFR, COX6B2, and serine synthesis pathway genes, and cooperates with lncRNAs/circRNAs that modulate its activity or protect it from ubiquitin-mediated degradation, while its re-expression in cancer (often driven by promoter demethylation or gene fusion/amplification) drives tumor proliferation, metastasis, metabolic reprogramming, immune evasion, and drug resistance across multiple cancer types.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IGF2BP3 is a multifunctional RNA-binding protein that acts primarily as an N6-methyladenosine (m6A) reader to post-transcriptionally stabilize oncogenic and metabolic mRNAs, while also mediating mRNA degradation of m7G-modified transcripts and regulating alternative splicing. Its RRM1 domain directly contacts RNA via dinucleotide recognition [PMID:30135093], while its KH domains mediate m6A reading and are critical for target mRNA stabilization; IGF2BP3 forms cytoplasmic RNP granules that sequester mRNAs (including HMGA2, MYC, CDK6, and cyclins) away from miRNA/AGO2-directed decay, and cooperates with Lin28b, HuR, Matrin3, and circRNAs (circRARS, circNEIL3, circNFATC3) to enhance target mRNA protection [PMID:24703842, PMID:26974154, PMID:31221665, PMID:38073586]. IGF2BP3 protein stability is itself tightly controlled by ubiquitin-proteasome regulation through E3 ligases Parkin (at K213), TRIM25, and HECTD4, counterbalanced by the deubiquitinase USP11, and its RNA-binding specificity is modulated by lactylation [PMID:37877353, PMID:37340423, PMID:35031058, PMID:33594305, PMID:39450426]. Beyond cancer — where it stabilizes diverse targets to drive proliferation, immune evasion, metabolic reprogramming, and drug resistance — IGF2BP3 functions physiologically in maternal mRNA stability prior to zygotic genome activation, trophoblast invasion, fetal hematopoietic development, and cardiomyocyte regeneration [PMID:32127635, PMID:24457969, PMID:31221665, PMID:37188676].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"The question of how IGF2BP3 protects target mRNAs from miRNA-mediated silencing was resolved by demonstrating it forms cytoplasmic RNP granules that physically sequester let-7 target mRNAs (HMGA2 and others) away from AGO/miRNA complexes, establishing a 'safe house' mechanism for post-transcriptional stabilization.\",\n      \"evidence\": \"Cytoplasmic granule characterization, antagomiR experiments, and global enrichment analysis in multiple cell types\",\n      \"pmids\": [\"24703842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Granule composition and biophysical properties (liquid-liquid phase separation vs. solid aggregates) not characterized\", \"Whether granule formation requires m6A marks was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"IGF2BP3 was shown to have a physiological role in trophoblast invasion, with loss of expression correlating with pre-eclampsia, establishing the gene's importance outside cancer contexts.\",\n      \"evidence\": \"In vitro invasion/migration assays, ex vivo placental explants, and expression comparison between normal and pre-eclamptic placentas\",\n      \"pmids\": [\"24457969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target mRNAs mediating trophoblast invasion were not identified\", \"Genetic evidence from human families is lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Contrary to its canonical stabilizing role, IGF2BP3 was found to also destabilize specific mRNAs (EIF4E-BP2, MEIS3) by interacting with ribonucleases XRN2 and exosome components, establishing that IGF2BP3 can promote mRNA decay in a context-dependent manner.\",\n      \"evidence\": \"RNA-seq of IGF2BP3-depleted cells, co-immunoprecipitation with ribonucleases, epistasis rescue experiments\",\n      \"pmids\": [\"26522719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines whether IGF2BP3 stabilizes vs. destabilizes a given transcript was not resolved\", \"Direct enzymatic reconstitution of the degradation pathway was not performed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CLIP-seq identified direct IGF2BP3 binding to MYC and CDK6 3ʹUTRs in leukemia, and functional studies showed this binding promotes hematopoietic progenitor proliferation in MLL-rearranged B-ALL, establishing IGF2BP3 as a key post-transcriptional oncogenic effector in hematopoietic malignancies.\",\n      \"evidence\": \"CLIP-seq, knockdown-induced apoptosis, enforced expression in murine bone marrow cells\",\n      \"pmids\": [\"26974154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether m6A modification of MYC/CDK6 mRNAs is required for IGF2BP3 binding was not tested in this study\", \"Contributions of individual RNA-binding domains were not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"IGF2BP3 was shown to cooperate with ILF3/NF90 and PTBP1 at cyclin D1/D3 3ʹUTRs to shield these transcripts from AGO2/GW182-mediated translational repression, extending the safe-house model to translational regulation and identifying specific protein co-factors.\",\n      \"evidence\": \"Co-immunoprecipitation demonstrating IMP3/ILF3/PTBP1 complex, epistasis with AGO2/GW182\",\n      \"pmids\": [\"27840950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding validation by CLIP for these partners at the same sites is lacking\", \"Nuclear localization dependence mechanism was not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The crystal structure of IGF2BP3 RRM1-RRM2 tandem domains revealed that only RRM1 directly contacts RNA (recognizing a dinucleotide), while the spatial arrangement between RRM1 and RRM2 is unique, providing the first structural basis for understanding IGF2BP3's RNA recognition.\",\n      \"evidence\": \"X-ray crystallography of IMP3 RRM12 alone and in complex with RNA, plus biochemical validation\",\n      \"pmids\": [\"30135093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of KH domains in complex with m6A-modified RNA are not available\", \"How RRM and KH domains cooperate in full-length protein remains unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The discovery that Lin28b and IGF2BP3 physically interact and co-bind thousands of mRNAs (including Pax5 and Arid3a) to jointly stabilize them revealed a cooperative developmental program; an autoregulatory loop where IGF2BP3 mRNA is itself a target was also identified.\",\n      \"evidence\": \"Proteomics, single-cell RNA-seq, enforced co-expression in adult HSPCs with in vivo fetal B-cell readout\",\n      \"pmids\": [\"31221665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Lin28b modifies IGF2BP3's m6A reading capacity was not tested\", \"The mechanism by which the autoregulatory loop is terminated during development is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Maternal Igf2bp3 was shown to be essential for stabilizing maternal mRNAs before the maternal-to-zygotic transition in zebrafish, with mutants displaying cytoskeletal and cell division defects, establishing a conserved developmental role in mRNA homeostasis.\",\n      \"evidence\": \"Maternal igf2bp3 mutant zebrafish, mRNA stability assays, phenotypic analysis\",\n      \"pmids\": [\"32127635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this maternal function depends on m6A reading was not determined\", \"Functional redundancy with IGF2BP1/2 in this context not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic deletion of Igf2bp3 in MLL-Af4 leukemia demonstrated it controls a post-transcriptional operon encompassing HOXA genes and Ras pathway transcripts, and also regulates pre-mRNA splicing — extending its function beyond mRNA stabilization to splicing regulation.\",\n      \"evidence\": \"Igf2bp3 deletion in mouse MLL-Af4 leukemia model, CLIP-seq, splicing analysis, leukemia-initiating cell transplantation\",\n      \"pmids\": [\"34321607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The splicing mechanism (direct spliceosome interaction vs. indirect) was not defined\", \"Whether splicing function requires m6A recognition was not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple studies established IGF2BP3 as a canonical m6A reader that stabilizes diverse m6A-modified mRNAs including PD-L1, anti-ferroptotic factors (GPX4, SLC3A2), and RCC2, linking m6A reading to immune evasion, ferroptosis resistance, and leukemia survival.\",\n      \"evidence\": \"MeRIP-seq, RIP-qPCR, domain mutant analysis, knockdown/rescue experiments across breast cancer, lung adenocarcinoma, and AML models\",\n      \"pmids\": [\"35197058\", \"36457846\", \"35217832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how KH domains distinguish m6A from unmodified adenosine is not resolved\", \"Whether all stabilization targets require m6A or whether some are m6A-independent is not systematically defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CircNEIL3 was found to stabilize IGF2BP3 protein by blocking HECTD4-mediated ubiquitination, revealing that circRNAs regulate IGF2BP3 at the protein stability level rather than through RNA target modulation.\",\n      \"evidence\": \"RNA pull-down, mass spectrometry, co-IP, ubiquitination assays in glioma models\",\n      \"pmids\": [\"35031058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The ubiquitination sites targeted by HECTD4 were not mapped\", \"Whether other circRNAs similarly prevent ubiquitination by distinct E3 ligases is not systematic\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A detailed ubiquitin-regulatory network was elucidated: Parkin ubiquitinates IGF2BP3 at K213 in the KH1 domain (critical for m6A reading), TRIM25 mediates ubiquitination blocked by circNFATC3, and USP11 counteracts degradation — establishing that IGF2BP3's m6A-binding and protein-level abundance are coordinately regulated by the ubiquitin-proteasome system.\",\n      \"evidence\": \"Mass spectrometry for K213 site, KH domain mutagenesis, Co-IP/ubiquitination assays, rescue experiments across cervical cancer, gastric cancer, and colorectal cancer models\",\n      \"pmids\": [\"37877353\", \"37340423\", \"33594305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the multiple E3 ligases are prioritized or whether they act on different pools of IGF2BP3 is unknown\", \"Whether K213 ubiquitination occurs in non-cancer contexts is not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CircRARS was shown to bind IGF2BP3 KH1-KH2 domains via a 12-nucleotide motif, enhancing m6A recognition and recruiting stabilizer proteins HuR, Matrin3, and pAbPC1, providing a mechanistic model for how circRNAs allosterically enhance IGF2BP3 function.\",\n      \"evidence\": \"Domain binding mapping, RNA pulldown with sequence-specific validation, RIP, stabilizer protein complex identification\",\n      \"pmids\": [\"38073586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HuR/Matrin3/pAbPC1 recruitment requires the circRNA or occurs independently is not fully dissected\", \"Single lab — awaits independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A mechanistically distinct function was discovered: IGF2BP3 preferentially binds internal m7G modifications via KH domains to promote degradation (not stabilization) of m7G-modified transcripts including TP53, resolving a long-standing puzzle about how IGF2BP3 can both stabilize and destabilize different mRNAs.\",\n      \"evidence\": \"In vitro binding assays comparing m7G vs. m6A preference, dCas13b site-specific m7G targeting, cancer phenotype readouts in glioblastoma\",\n      \"pmids\": [\"39198433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The degradation effector machinery recruited by IGF2BP3 at m7G sites is not identified\", \"Genome-wide scope of m7G-dependent IGF2BP3 degradation targets is not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Lactylation of IGF2BP3 at lysine residues was identified as a post-translational modification that modulates its RNA-binding specificity, enabling capture of PCK2 and NRF2 mRNAs and creating a metabolic feedback loop driving drug resistance in hepatocellular carcinoma.\",\n      \"evidence\": \"Lysine lactylation detection, RIP, metabolomics linking lactylated IGF2BP3 to serine/SAM metabolism, in vivo siRNA delivery in lenvatinib-resistant models\",\n      \"pmids\": [\"39450426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific lactylation sites and the lactylation writer enzyme are not identified\", \"Whether lactylation broadly rewires IGF2BP3 target specificity beyond PCK2/NRF2 is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IGF2BP3 was shown to stabilize m6A-modified serine synthesis pathway mRNAs (ATF4, PHGDH, PSAT1) in AML, revealing a metabolic dependency exploitable by serine restriction, and extending the functional scope to cancer metabolism.\",\n      \"evidence\": \"CRISPR/Cas9 screen, RIP/m6A validation, in vivo AML models with dietary serine/glycine deprivation\",\n      \"pmids\": [\"40328743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this metabolic function is shared with IGF2BP1/2 is untested\", \"The therapeutic window of serine restriction in patients is not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IGF2BP3 was found to synergize with NONO in m6A-dependent alternative splicing of DLG1 by disrupting the RBM14-NONO inhibitory interaction, providing a molecular mechanism for IGF2BP3's splicing regulatory function.\",\n      \"evidence\": \"mRNA-seq, RIP-seq, Co-IP/mass spectrometry, PSI analysis, YAP1/JUN pathway readouts in gallbladder cancer\",\n      \"pmids\": [\"38341127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this splicing mechanism operates beyond DLG1 and gallbladder cancer is unknown\", \"How m6A marks at splice sites recruit IGF2BP3 vs. other readers is not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and biophysical model explaining how IGF2BP3 discriminates between m6A-stabilization and m7G-degradation modes, how its multiple post-translational modifications (ubiquitination, lactylation) intersect, and the full scope of its physiological vs. oncogenic target repertoire remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length IGF2BP3 structure with m6A- or m7G-modified RNA\", \"No systematic comparison of IGF2BP3 targets across normal development vs. cancer\", \"How circRNA binding, PTMs, and protein co-factors combinatorially specify IGF2BP3 output is not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 5, 6, 12, 16, 17, 20, 21, 27, 33]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [11, 39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 15, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 13, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 5, 6, 11, 16, 17, 20, 21, 33]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 24, 25, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [33, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 16, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LIN28B\",\n      \"ILF3\",\n      \"PTBP1\",\n      \"USP11\",\n      \"PARK2\",\n      \"TRIM25\",\n      \"HECTD4\",\n      \"NONO\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IGF2BP3 is an oncofetal RNA-binding protein that functions as a major N6-methyladenosine (m6A) reader, using its KH domains to recognize GG(m6A)C motifs on thousands of mRNA targets and predominantly stabilizing them—including MYC, CDK6, HMGA2, EGFR, PD-L1, and serine synthesis pathway transcripts—thereby promoting proliferation, immune evasion, metabolic reprogramming, and drug resistance across diverse cancers [PMID:29476152, PMID:26974154, PMID:35197058, PMID:40328743]. Beyond m6A-dependent stabilization, IGF2BP3 can destabilize specific mRNAs through interaction with ribonucleases XRN2 and the exosome or via recognition of internal m7G modifications, and it regulates alternative splicing in concert with NONO [PMID:26522719, PMID:39198433, PMID:38341127]. IGF2BP3 protein turnover is tightly controlled by ubiquitination through multiple E3 ligases (TRIM25, HECTD4, Parkin at K213) counterbalanced by USP11-mediated deubiquitination, while circRNAs (circNFATC3, circNEIL3, circRARS) and the post-translational modification lysine lactylation modulate its stability and RNA-binding activity [PMID:33436560, PMID:37877353, PMID:35031058, PMID:39450426]. During normal development, IGF2BP3 is essential for maternal mRNA stability during the zebrafish maternal-to-zygotic transition and cooperates with LIN28B to drive fetal-like B-cell lymphopoiesis, while its aberrant re-expression in adult tissues is a hallmark of MLL-rearranged leukemia and numerous solid tumors [PMID:32127635, PMID:31221665, PMID:34321607].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The initial characterization of IGF2BP3 as an IGF-II mRNA-binding protein with two RRM and four KH domains that represses IGF-II leader 3 mRNA translation established it as a developmentally regulated post-transcriptional regulator.\",\n      \"evidence\": \"RNA binding assays, luciferase translational reporter, immunolocalization in human/mouse embryos\",\n      \"pmids\": [\"9891060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target repertoire beyond IGF-II unknown\", \"No structural detail of RNA recognition\", \"Mechanism of translational repression not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The discovery that IGF2BP3-containing cytoplasmic granules exclude AGO/miRNAs and shield let-7 target mRNAs (HMGA2, LIN28B) from miRNA-mediated decay revealed a 'safe house' mechanism of mRNA stabilization distinct from direct translational control.\",\n      \"evidence\": \"Granule fractionation, RIP, let-7 antagomiR experiments, 3′UTR let-7 site deletion, IMP1-KO mouse embryos\",\n      \"pmids\": [\"24703842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of safe-house granules not fully defined\", \"Whether miRNA exclusion is active or passive unclear\", \"Applicability beyond let-7 targets not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that IGF2BP3 can destabilize mRNAs (EIF4E-BP2, MEIS3) by recruiting XRN2 and exosome components overturned the assumption that it exclusively stabilizes targets, revealing context-dependent polarity of its post-transcriptional effects.\",\n      \"evidence\": \"RNA-seq, RIP-seq, co-IP with ribonucleases, mRNA stability assays, rescue experiments in lung adenocarcinoma\",\n      \"pmids\": [\"26522719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines stabilization versus destabilization for a given target\", \"Whether ribonuclease recruitment requires cofactors\", \"Structural basis of XRN2/exosome interaction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CLIP-seq identification of MYC and CDK6 as direct IGF2BP3 targets in MLL-rearranged B-ALL, combined with in vivo mouse hematopoietic models, established IGF2BP3 as a functionally essential oncogene in leukemia with defined downstream effectors.\",\n      \"evidence\": \"CLIP-seq, 3′UTR reporters, mouse BM transplant, knockdown in B-ALL lines\",\n      \"pmids\": [\"26974154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IGF2BP3 re-activation in MLL-rearranged leukemia not resolved\", \"Relative contribution of MYC versus CDK6 to leukemogenesis not separated\", \"Translational versus stability regulation on these targets not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The landmark identification of IGF2BP1/2/3 as a new class of m6A readers that stabilize thousands of m6A-marked mRNAs via their KH domains unified prior observations under an epitranscriptomic framework and distinguished IGF2BPs from decay-promoting YTHDF readers.\",\n      \"evidence\": \"m6A-seq, PAR-CLIP, RIP, KH domain mutagenesis, MYC mRNA stability assays\",\n      \"pmids\": [\"29476152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KH domains specifically recognize m6A versus unmethylated RNA structurally undefined\", \"Whether all four KH domains contribute equally unknown\", \"Relative m6A-dependent versus m6A-independent binding proportions unquantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Crystal structure of the RRM1-RRM2 tandem revealed that only RRM1 contacts RNA via a dinucleotide recognition mode, with a unique inter-domain orientation, providing the first atomic-resolution view of IGF2BP3-RNA recognition.\",\n      \"evidence\": \"X-ray crystallography with biochemical RNA-binding validation\",\n      \"pmids\": [\"30135093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of KH domains or full-length protein\", \"How RRM and KH domains cooperate on a single mRNA unknown\", \"Structure of m6A-bound complex not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"LIN28B and IGF2BP3 were shown to physically interact and co-stabilize thousands of mRNAs in fetal B-cell progenitors, jointly driving fetal-like lymphopoiesis more efficiently than either factor alone, revealing a cooperative post-transcriptional program in normal hematopoiesis.\",\n      \"evidence\": \"Proteomics, in situ analysis, CLIP/RIP-seq, in vivo mouse HSPC transplantation, scRNA-seq\",\n      \"pmids\": [\"31221665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LIN28B-IGF2BP3 interaction is direct or RNA-mediated not fully resolved\", \"Autoregulatory loop mechanism not structurally characterized\", \"Relevance to leukemia initiation not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Maternal-specific igf2bp3 deletion in zebrafish causing embryonic lethality through destabilization of maternal mRNAs established that IGF2BP3's mRNA-stabilizing function is essential for vertebrate embryogenesis, not only cancer.\",\n      \"evidence\": \"Maternal mutant zebrafish, RNA-seq, mRNA half-life measurements, gain- and loss-of-function\",\n      \"pmids\": [\"32127635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian maternal-zygotic transition depends on IGF2BP3 similarly untested\", \"Specific target mRNAs critical for cytokinesis not identified\", \"Redundancy with IGF2BP1/2 in this context unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic deletion of Igf2bp3 in an MLL-Af4 leukemia mouse model significantly extended survival with minimal effect on normal hematopoiesis, validating IGF2BP3 as a therapeutic target and revealing its regulation of Hoxa genes and Ras pathway mRNAs including pre-mRNA splicing.\",\n      \"evidence\": \"Conditional knockout in mouse MLL-Af4 leukemia model, CLIP-seq, RNA-seq, leukemia-initiating cell assays\",\n      \"pmids\": [\"34321607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IGF2BP3 regulates splicing mechanistically not defined\", \"Whether pharmacological inhibition recapitulates genetic deletion unknown\", \"Splicing versus stability contribution to leukemogenesis not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of TRIM25 as an E3 ligase that ubiquitinates IGF2BP3 for proteasomal degradation—scaffolded by the circRNA circNDUFB2—established the first ubiquitin-dependent regulatory mechanism controlling IGF2BP3 protein turnover.\",\n      \"evidence\": \"RIP, RNA pulldown, co-IP, ubiquitination assays, m6A analysis, in vivo assays\",\n      \"pmids\": [\"33436560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitination sites by TRIM25 not mapped\", \"Whether other circRNAs similarly scaffold E3 ligases for IGF2BP3 unknown\", \"Physiological versus cancer-specific relevance of this pathway unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple studies converged to define IGF2BP3's ubiquitin regulatory network: HECTD4 and Parkin (ubiquitination at K213 in KH1) promote degradation while USP11 deubiquitinates and stabilizes it, and circRNAs (circNEIL3, circNFATC3) competitively block ubiquitination, establishing IGF2BP3 protein level as a tightly controlled node.\",\n      \"evidence\": \"Co-IP, mass spectrometry site mapping (K213), in vitro/in vivo ubiquitination assays, circRNA binding competition, xenograft models\",\n      \"pmids\": [\"37877353\", \"35031058\", \"37340423\", \"33594305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among E3 ligases in different tissues not established\", \"Whether K213 ubiquitination is the sole functional site unknown\", \"Interplay between lactylation and ubiquitination at nearby residues not explored\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"IGF2BP3's m6A reader function was shown to stabilize PD-L1 mRNA downstream of METTL3, directly linking epitranscriptomic mRNA regulation to tumor immune evasion and providing a mechanistic basis for immune checkpoint resistance.\",\n      \"evidence\": \"MeRIP-seq, RIP-qPCR, METTL3/IGF2BP3 knockdown, T cell co-culture, mouse xenografts\",\n      \"pmids\": [\"35197058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF2BP3 stabilizes other immune checkpoint mRNAs not tested\", \"Patient response to immunotherapy correlation not established\", \"Structural basis of m6A-PD-L1 mRNA recognition unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The discovery that IGF2BP3 preferentially binds internal m7G-modified mRNAs and promotes their degradation (including TP53 mRNA) revealed a second epitranscriptomic reading modality with opposite functional polarity to its m6A reader activity.\",\n      \"evidence\": \"m7G-modified RNA pull-down, binding assays, dCas13b site-specific targeting, mRNA half-life assays in glioblastoma\",\n      \"pmids\": [\"39198433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for m7G versus m6A discrimination unknown\", \"Genome-wide scope of m7G-dependent destabilization not mapped\", \"Whether m6A and m7G marks on the same transcript compete for IGF2BP3 binding untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CircRARS was found to bind IGF2BP3 KH1-KH2 domains via a specific 12-nt motif, enhancing m6A recognition and recruiting stabilizer proteins HuR, Matrin3, and pAbPC1, defining a circRNA-mediated mechanism that augments IGF2BP3's m6A reader activity.\",\n      \"evidence\": \"RIP, RNA pulldown, domain mapping, m6A binding assays, identification of GUCUUCCAGCAA binding motif\",\n      \"pmids\": [\"38073586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether circRARS allosterically changes KH domain conformation or acts as a scaffold uncertain\", \"Generalizability of this 12-nt motif to other circRNAs not tested\", \"Stoichiometry of the circRARS/IGF2BP3/stabilizer complex unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Lysine lactylation of IGF2BP3 was identified as a glycolysis-driven post-translational modification that enhances its mRNA-binding capacity and creates a positive feedback loop with m6A methylation (via SAM availability), connecting metabolic state to epitranscriptomic regulation in drug-resistant HCC.\",\n      \"evidence\": \"Lactylation assays, RIP, MeRIP, metabolomics, lenvatinib-resistant in vivo models\",\n      \"pmids\": [\"39450426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific lactylated residues on IGF2BP3 not mapped\", \"Whether lactylation competes with ubiquitination at the same lysines unknown\", \"Relevance beyond lenvatinib resistance not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A CRISPR screen revealed that IGF2BP3 sustains the serine synthesis pathway by stabilizing m6A-marked ATF4, PHGDH, and PSAT1 mRNAs in AML, and combined IGF2BP3 depletion with dietary serine/glycine restriction potently suppressed leukemia while sparing normal hematopoiesis, defining a metabolic vulnerability.\",\n      \"evidence\": \"CRISPR/Cas9 screen, RIP, mRNA stability, metabolomics, dietary restriction in vivo AML models\",\n      \"pmids\": [\"40328743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this metabolic dependency extends to solid tumors unknown\", \"Pharmacological IGF2BP3 inhibitor for clinical translation not available\", \"Mechanism by which normal HSPCs compensate for IGF2BP3 loss unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full structural understanding of how IGF2BP3 discriminates m6A from m7G modifications, how its six RNA-binding domains cooperate on a single mRNA, and whether selective pharmacological inhibition can recapitulate the therapeutic window seen with genetic deletion remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length or KH-domain m6A-bound structure exists\", \"No selective small-molecule IGF2BP3 inhibitor reported\", \"Rules governing stabilization versus destabilization of individual target mRNAs undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7, 12, 24, 27]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 10, 27, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 7, 14, 27, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 43, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 14, 17, 40]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [23, 36, 40]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 20, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LIN28B\",\n      \"TRIM25\",\n      \"NONO\",\n      \"USP11\",\n      \"XRN2\",\n      \"PRKN\",\n      \"ILF3\",\n      \"PTBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}