{"gene":"IGF2BP3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2016,"finding":"IGF2BP3 modulates miRNA-mRNA interactions by promoting association of the RNA-induced silencing complex (RISC) with specific transcripts in pancreatic ductal adenocarcinoma cells; iCLIP revealed significant overlap of IGF2BP3 and microRNA binding sites, and loss of IGF2BP3 reduced cell invasiveness and remodeled focal adhesion junctions.","method":"iCLIP (individual nucleotide resolution crosslinking immunoprecipitation), genome-wide approaches, loss-of-function assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genome-wide iCLIP with functional validation (invasion, focal adhesion remodeling), single lab with multiple orthogonal methods","pmids":["27210763"],"is_preprint":false},{"year":2016,"finding":"IGF2BP3 directly targets oncogenic transcripts MYC and CDK6 via elements within 3' UTRs to stabilize them, promoting hematopoietic progenitor proliferation and survival; enforced IGF2BP3 expression in mice enhanced Myc and Cdk6 expression in bone marrow.","method":"Cross-link immunoprecipitation and high-throughput sequencing (CLIP-seq), knockdown/enforced expression in murine BM cells, in vivo mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal CLIP-seq with in vivo validation, single lab with multiple orthogonal methods","pmids":["26974154"],"is_preprint":false},{"year":2015,"finding":"IGF2BP3 destabilizes EIF4E-BP2 and MEIS3 mRNAs through interaction with ribonucleases XRN2 and exosome components (co-IP), thereby facilitating eIF4E-mediated translational activation and promoting cell proliferation.","method":"RNA immunoprecipitation followed by massively parallel sequencing, co-immunoprecipitation with XRN2 and exosome components, IGF2BP3 depletion rescue experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP identifying ribonuclease partners, sequencing-based target identification, functional rescue; single lab with multiple orthogonal methods","pmids":["26522719"],"is_preprint":false},{"year":2014,"finding":"IGF2BP3 and IGF2BP3-bound transcripts (ARF6 and ARHGEF4) localize to cytoplasmic RNA granules accumulating in membrane protrusions of pancreatic cancer cells, where they are preferentially translated to induce further protrusion formation, promoting cell invasiveness and tumor metastasis.","method":"Subcellular fractionation/localization imaging, translation assays in membrane protrusions, in vivo metastasis model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — localization tied to functional consequence (invasion/metastasis), single lab with multiple methods","pmids":["25216519"],"is_preprint":false},{"year":2017,"finding":"IGF2BP3 (neonatal-specific expression) prevents destabilization of nuclear RNA 7SK, thereby blocking P-TEFb activation in neonatal megakaryocytes and restricting adult-type megakaryocyte morphogenesis; IGF2BP3 knockdown conferred adult-type phenotypic and molecular features on neonatal megakaryocytes.","method":"Knockdown in neonatal progenitors, phenotypic assays (polyploidization, proplatelet formation), molecular analysis of 7SK RNA stability","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and mechanistic link to 7SK/P-TEFb, single lab with multiple orthogonal assays","pmids":["28481226"],"is_preprint":false},{"year":2019,"finding":"Lin28b directly interacts with IGF2BP3 (shown by proteomics and in situ analyses), and together they stabilize thousands of mRNAs including Pax5 and Arid3a by binding at the same sites; IGF2BP3 mRNA itself is a target, forming an autoregulatory loop that mediates fetal-adult hematopoietic switch.","method":"Proteomics, in situ interaction analyses, single-cell RNA sequencing, enforced co-expression in adult HSPCs","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomics + in situ validation + functional co-expression, single lab with multiple orthogonal methods","pmids":["31221665"],"is_preprint":false},{"year":2021,"finding":"IGF2BP3 regulates a posttranscriptional operon in MLL-Af4 leukemia, controlling steady-state mRNA levels of Hoxa locus genes and Ras signaling pathway transcripts, and unexpectedly also regulates pre-mRNA splicing; Igf2bp3 deletion significantly increases survival of MLL-Af4 leukemia mice.","method":"Genetic deletion (Igf2bp3 knockout) in mouse leukemia model, RNA-seq, splicing analysis, in vivo survival assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined in vivo phenotype, RNA-seq, splicing analysis; single lab with multiple orthogonal methods and robust in vivo data","pmids":["34321607"],"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, D3 and G1 mRNAs and protect them from translational repression induced by miRNA-dependent recruitment of AGO2/GW182 complex; this regulation depends on nuclear localization of IMP-3.","method":"Knockdown experiments, polyribosome association assays, co-immunoprecipitation with AGO2/GW182","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional interaction with RISC components shown, nuclear localization requirement demonstrated, single lab","pmids":["27840950"],"is_preprint":false},{"year":2019,"finding":"IGF2BP3 competitively occupies the miR-3614-3p binding site on TRIM25 mRNA 3'UTR and inhibits miR-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation and promoting breast cancer cell proliferation.","method":"Luciferase activation assays, RNA immunoprecipitation (RIP), biotin pull-down assays, in vitro and in vivo loss/gain-of-function","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP and pulldown with functional validation, single lab, multiple methods","pmids":["30797711"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, Igf2bp3 maintains maternal mRNA stability prior to the maternal-to-zygotic transition; depletion of maternal igf2bp3 destabilizes maternal mRNAs and causes abnormal cytoskeleton organization and cell division, while overexpression enhances stability of target maternal mRNAs.","method":"Maternal igf2bp3 mutant zebrafish, mRNA stability assays, GO analysis, overexpression experiments","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic mutant with defined developmental phenotype, mRNA stability assays, overexpression rescue; multiple orthogonal approaches","pmids":["32127635"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, Igf2bp3 loss leads to expanded yolk syncytial layer, reduced germline RNA expression, translational de-regulation of a Nodal reporter during mid-blastula transition, and defects in primordial germ cell behavior and germ cell death; adult igf2bp3 mutants show strong male bias.","method":"Igf2bp3 maternal/zygotic mutants, Nodal reporter assay, RNA/PGC analysis, adult phenotype assessment","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic mutant with multiple defined phenotypes at molecular and cellular level, translational reporter assay","pmids":["34214072"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A modification of PD-L1 mRNA is read by IGF2BP3, which stabilizes PD-L1 mRNA; IGF2BP3 knockdown reduced PD-L1 mRNA stability and enhanced anti-tumor T cell activity in vitro and in vivo.","method":"MeRIP-seq, MeRIP-qPCR, RIP-qPCR, m6A quantification, xenograft mouse models, knockdown experiments","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq, RIP-qPCR, and in vivo validation; single lab with multiple orthogonal methods","pmids":["35197058"],"is_preprint":false},{"year":2020,"finding":"IGF2BP3 acts as an m6A reader that binds to m6A-modified CCND1 mRNA in its CDS region to regulate mRNA stability, and similarly reads m6A modification on VEGF mRNA to regulate its stability; knockdown of IGF2BP3 repressed S-phase entry and angiogenesis in colon cancer.","method":"RNA immunoprecipitation (RIP), m6A RNA immunoprecipitation (MeRIP), cell cycle flow cytometry, rescue experiments with CCND1 overexpression","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP and MeRIP with functional rescue, single lab","pmids":["32993738"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 interacts with RCC2 mRNA and stabilizes m6A-modified RCC2 mRNA in AML cells; IGF2BP3 knockdown suppressed AML cell survival, proliferation, and leukemic capacity in vitro and in vivo.","method":"RNA immunoprecipitation, m6A modification assays, knockdown in AML cell lines, in vivo leukemia models","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP with m6A assay and in vivo validation, single lab","pmids":["35217832"],"is_preprint":false},{"year":2023,"finding":"Parkin (E3 ubiquitin ligase) directly interacts with IGF2BP3 and ubiquitinates it at K213 in the first KH domain, leading to proteasomal degradation; K213 mutation abolishes IGF2BP3's oncogenic function as an m6A reader and inactivates PI3K and MAPK signaling.","method":"Co-immunoprecipitation, in vivo and in vitro ubiquitination assays, mass spectrometry (ubiquitination site identification), RNA immunoprecipitation, xenograft mouse model","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro/in vivo ubiquitination assay, MS-identified modification site, functional mutagenesis, multiple orthogonal methods","pmids":["37877353"],"is_preprint":false},{"year":2023,"finding":"circNEIL3 (and other circRNAs) stabilize IGF2BP3 protein by preventing HECTD4-mediated ubiquitination; this protects IGF2BP3 from proteasomal degradation in glioma cells.","method":"RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), co-immunoprecipitation assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pulldown, MS, Co-IP showing interaction with HECTD4; single lab","pmids":["35031058"],"is_preprint":false},{"year":2023,"finding":"circNFATC3 binds to IGF2BP3 and prevents TRIM25-mediated ubiquitination, thereby enhancing IGF2BP3 protein stability and enabling it to promote CCND1 mRNA stability in gastric cancer cells.","method":"RIP, RNA-FISH/IF, IP, rescue experiments, co-immunoprecipitation","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and RIP showing mechanistic interaction, single lab","pmids":["37340423"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 enhances translational efficiency of COPS7B mRNA to promote colorectal cancer growth and metastasis; COPS7B interacts with ribosomes to facilitate ribosome biogenesis and mRNA translation initiation.","method":"RIP-seq, ribosome-protected mRNA analysis (ribosome profiling), proteomics, functional assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome profiling combined with proteomics and RIP-seq; single lab","pmids":["37560971"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 preferentially binds internal mRNA m7G modifications and, unlike its m6A-binding activity which stabilizes transcripts, IGF2BP3-m7G interaction promotes degradation of m7G-modified target transcripts including TP53 in cancer cells.","method":"In vitro binding assays, m7G modification assays, IGF2BP3 knockdown/modulation, dCas13b-guided site-specific m7G targeting, mRNA half-life measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding, site-specific m7G targeting, mRNA stability assays with functional consequence; multiple orthogonal methods in single rigorous study","pmids":["39198433"],"is_preprint":false},{"year":2024,"finding":"Lysine lactylation of IGF2BP3 (driven by increased glycolysis/lactate accumulation) is required for capturing PCK2 and NRF2 mRNAs, enhancing their expression and reprogramming serine metabolism; this lactylated IGF2BP3-PCK2-SAM-m6A loop promotes lenvatinib resistance in HCC.","method":"Lactylation modification assays, RIP assays, in vitro and in vivo lenvatinib-resistant models, siRNA liposome delivery","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — novel PTM (lactylation) identified with functional consequence, RIP assays; single lab","pmids":["39450426"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 binds to the 3'-UTR of COX6B2 mRNA in an m6A-dependent manner to increase COX6B2 mRNA stability, promoting oxidative phosphorylation and EGFR-TKI resistance in non-small cell lung cancer.","method":"RIP, MeRIP, mRNA stability assays, in vitro/in vivo EGFR-TKI resistance models, patient-derived xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP + MeRIP + functional rescue in patient-derived xenograft; multiple orthogonal methods, single lab","pmids":["37061993"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 binds m6A-modified MCM5 mRNA to prolong its stability, upregulating MCM5 protein which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizing NICD1 and activating Notch signaling to promote partial EMT in lung adenocarcinoma.","method":"MeRIP-seq, RIP, mRNA stability assay, co-immunoprecipitation, in vitro and in vivo functional assays, clinical LUAD specimen correlation","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP, RIP, and mechanistic Co-IP; single lab with multiple orthogonal methods","pmids":["37171793"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 binds to and stabilizes m6A-modified NRF2 mRNA (identified by RIP and RNA pulldown), preventing ferroptosis in hepatocellular carcinoma; IGF2BP3 knockdown promoted ferroptosis and sensitized HCC cells to sorafenib.","method":"RIP, RNA pulldown, m6A reader activity assay, ferroptosis markers (ROS, Fe2+, MDA), in vivo experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP and pulldown with functional ferroptosis readouts; single lab","pmids":["36030651"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 binds to and stabilizes m6A-modified mRNAs of anti-ferroptotic factors (GPX4, SLC3A2, ACSL3, FTH1) in an m6A reading domain-dependent manner in lung adenocarcinoma, desensitizing cells to ferroptosis.","method":"RIP, MeRIP, mRNA stability assay, IGF2BP3 overexpression, correlation in clinical LUAD specimens","journal":"Materials today. Bio","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP and MeRIP with functional validation, single lab","pmids":["36457846"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 stabilizes MMP3 mRNA through interaction with N6-methyladenosine modification; IGF2BP3 expression is upregulated after cardiac injury and both gain- and loss-of-function analyses show it regulates cardiomyocyte proliferation in vitro and in vivo, promoting cardiac regeneration after myocardial infarction.","method":"RIP, m6A modification assays, gain/loss-of-function in mouse myocardial infarction model, cardiomyocyte proliferation assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP with m6A interaction shown and in vivo cardiac model; single lab with multiple orthogonal methods","pmids":["37188676"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 stabilizes GLI2 mRNA by targeting its m6A site; stabilized GLI2 then transcriptionally promotes SYVN1, which ubiquitinates and degrades PPARα, inhibiting PPARα-mediated autophagy and exacerbating liver injury in sepsis.","method":"RIP, m6A assays, ChIP-qPCR, knockdown experiments in vitro and in cecal ligation and puncture mouse model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP + ChIP + in vivo model; single lab with multiple methods","pmids":["38799573"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 recognizes m6A on mRNAs of key serine synthesis pathway genes (ATF4, PHGDH, PSAT1), stabilizing these transcripts to sustain serine production; IGF2BP3 silencing combined with dietary serine/glycine restriction potently inhibits AML in vitro and in vivo while sparing normal hematopoiesis.","method":"CRISPR/Cas9 screen, RIP, mRNA stability assays, dietary restriction mouse models, AML in vivo experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen + RIP + dietary restriction in vivo; multiple orthogonal methods with in vivo validation","pmids":["40328743"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 promotes CAMK1 mRNA stability via m6A modification (MeRIP and RIP assays); IGF2BP3-CAMK1 axis inhibits mitochondrial fission to alleviate diabetic nephropathy progression in vitro and in vivo.","method":"MeRIP assay, RIP assay, dual-luciferase reporter, actinomycin D mRNA stability assay, CAMK1 conditional KO mice, STZ diabetic mouse model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP + RIP + conditional KO mouse model; single lab with multiple orthogonal methods","pmids":["38216068"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 recognizes m6A modification on HIF1A mRNA, increasing HIF1A RNA stability and expression; stabilized HIF1A activates RhoA/YAP signaling to promote hepatocyte reprogramming in acute-on-chronic liver failure.","method":"m6A dot assay, m6A-antibody precipitation PCR, overexpression and knockdown in HepG2/Hep3B cells, EdU staining, sphere formation assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — m6A RIP with functional downstream validation; single lab","pmids":["37257765"],"is_preprint":false},{"year":2024,"finding":"WTAP-mediated m6A modification of ULK1 mRNA is recognized and stabilized by IGF2BP3 in an m6A-dependent manner, leading to elevated ULK1 expression and enhanced mitophagy in epithelial ovarian cancer.","method":"MeRIP assay, RIP assay, knockdown/overexpression, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MeRIP + RIP assays with functional validation; single lab","pmids":["38286802"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 enhances mRNA stability of HMGB1 by binding to its mRNA (RIP assay), promoting inflammation and bladder cancer progression; pharmacological inhibition of HMGB1 reverses IGF2BP3 overexpression-induced cancer-promoting effects.","method":"RNA immunoprecipitation (RIP), mRNA stability assays, proliferation/migration/invasion assays, xenograft model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP with mRNA stability assay and in vivo model; single lab","pmids":["38504159"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 interacts with MYLK mRNA in an m6A-dependent manner, extending its half-life and inhibiting ERK1/2 phosphorylation, thereby repressing MSC adipogenesis; IGF2BP3 overexpression via AAV in adipose tissue reduced body weight and improved insulin resistance in high-fat diet mice.","method":"RIP, m6A interaction assay, mRNA half-life assay, MSC differentiation assays, AAV-mediated overexpression in mice","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + mRNA stability + in vivo AAV model; single lab with multiple methods","pmids":["38196046"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 enhances RRM2 mRNA stability by reading its m6A modification (MeRIP assay), promoting HCC cell malignant behaviors and M2 macrophage polarization by suppressing ferroptosis; FOXM1 is an upstream transcriptional activator of IGF2BP3 (ChIP + dual-luciferase).","method":"MeRIP, RIP, ChIP, dual-luciferase reporter, Co-IP, ferroptosis assays (MDA, GSH, ROS, lipid ROS), flow cytometry, xenograft model","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP + RIP + ChIP + in vivo model; single lab with multiple orthogonal methods","pmids":["39630361"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 promotes m6A-dependent stabilization of EGFR mRNA in cooperation with METTL14, activating the EGFR pathway and mediating cetuximab resistance in colorectal cancer.","method":"MeRIP, RIP, mRNA stability assay, co-immunoprecipitation with METTL14, functional assays, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MeRIP + RIP + Co-IP with writer protein; single lab","pmids":["37658049"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 binds to and destabilizes m6A-methylated SLIT2 mRNA in triple-negative breast cancer, impairing SLIT2/ROBO1 signaling and triggering activation of PI3K/AKT and MEK/ERK pathways to promote metastasis.","method":"RIP, MeRIP, mRNA stability assay, in vivo metastasis model, functional migration/invasion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP and MeRIP with in vivo validation; single lab","pmids":["36250924"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 regulates NFAT1 mRNA stability and translation in an m6A-dependent manner; NFAT1 induced by IGF2BP3 acts as a transcription factor to suppress IRF1 expression, inactivating interferon signaling and promoting gastric cancer progression.","method":"Ribo-seq, RNA-seq, m6A-seq, gain/loss-of-function experiments, mRNA stability assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics (Ribo-seq + RNA-seq + m6A-seq) with functional validation; single lab","pmids":["38448411"],"is_preprint":false},{"year":2023,"finding":"In neuroblastoma, IGF2BP3 and MYCN form a positive feedback loop: IGF2BP3 stabilizes MYCN mRNA via m6A modification, while MYCN acts as a transcription factor that directly promotes IGF2BP3 expression.","method":"RIP, MeRIP, ChIP assays, knockdown/overexpression in vitro and in vivo","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP + MeRIP + ChIP; single lab","pmids":["37156775"],"is_preprint":false},{"year":2023,"finding":"circRARS binds to KH1-KH2 domains of IGF2BP3 (12-nt sequence GUCUUCCAGCAA identified as binding site), enhancing m6A modification recognition; the IGF2BP3/circRARS complex stabilizes target mRNAs (CAPN15, CD44, HMGA2, TNRC6A, ZMIZ2) by recruiting stabilizer proteins HuR, Matrin3, and pAbPC1.","method":"RIP, RNA pull-down, domain mapping, mRNA stability assays, co-immunoprecipitation, in vitro and in vivo experiments","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain-level binding site identified, RIP with stabilizer protein recruitment; single lab","pmids":["38073586"],"is_preprint":false},{"year":2024,"finding":"WTAP-mediated m6A modification of GBE1 mRNA is stabilized by IGF2BP3 through RIP-confirmed interaction; WTAP/IGF2BP3 axis increases GBE1 mRNA stability and expression to promote pancreatic cancer cell proliferation and stemness via c-Myc.","method":"RIP assay, RNA stability experiments, Western blot, functional assays, subcutaneous/orthotopic mouse models","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP + stability assay + in vivo model; single lab","pmids":["38961325"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 upregulation in glioma enhances expression of E3 ubiquitin ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway, resulting in increased m6A-mediated CSF3 release and NET formation (NETosis); BET inhibitor reduces IGF2BP3 expression via BRD4/CDK9/RPB-1.","method":"IGF2BP3 overexpression/knockdown, ubiquitin-proteasome pathway assays, m6A assays, in vivo glioma models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic pathway linking IGF2BP3 to FTO/m6A/NETosis demonstrated; single lab","pmids":["38167409"],"is_preprint":false},{"year":2024,"finding":"WTAP-mediated m6A modification of EGR1 mRNA requires IGF2BP3 as a reader for recognition and stability; loss of WTAP decreases m6A on EGR1 mRNA, reducing IGF2BP3 binding and EGR1 mRNA stability, leading to decreased PTEN expression and promoting endometrial cancer stem cell traits.","method":"m6A modification assays, RIP, Western blot, gain-of-function rescue experiments in vivo","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic m6A reader function demonstrated with in vivo rescue; single lab","pmids":["39044249"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 deficiency in hepatic stellate cells reduces m6A content in Jagged1 (Jag1) mRNA, decreasing Notch/Hes1 signaling and GPX4 levels, thereby promoting ferroptosis in HSCs and reducing liver fibrosis.","method":"IGF2BP3 knockout mouse, multi-omics analysis, m6A quantification of Jag1, in vitro and in vivo ferroptosis assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse + multi-omics + ferroptosis assays; single lab with multiple methods","pmids":["39113232"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 promotes LDHA mRNA stability via m6A binding (RIP confirmed), increasing lactate accumulation and impairing CD8+ T cell anti-tumor immunity in gastric cancer.","method":"RIP, mRNA stability assay, co-culture system with CD8+ T cells, functional assays","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP with functional immune co-culture readout; single lab","pmids":["39397122"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 promotes m6A-dependent stabilization of SENP1 mRNA (3'UTR binding confirmed by MERIP-qPCR and RIP-qPCR), enhancing SENP1 expression which de-SUMOylates HDAC2 to activate EGFR transcription and the AKT pathway in AML.","method":"MERIP-qPCR, RIP-qPCR, CO-IP, RNA pulldown, dual-luciferase reporter, ChIP-qPCR","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MeRIP + RIP + Co-IP identifying mechanistic axis; single lab","pmids":["38822351"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 binds to m6A-modified RASGRF1 mRNA to stabilize it, activating mTORC1 signaling in RA fibroblast-like synoviocytes; IGF2BP3 knockout in mice ameliorated arthritis joint injury and reduced inflammatory infiltration.","method":"RIP, MeRIP, IGF2BP3 KO mouse arthritis model (K/BxN serum transfer), transfection experiments","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + MeRIP + KO mouse model; single lab with multiple methods","pmids":["40355406"],"is_preprint":false},{"year":2023,"finding":"IGF2BP3 promotes m6A-dependent stabilization of CLDN4 mRNA in gallbladder cancer, activating NF-κB signaling; overexpression of IGF2BP3 also promotes M2 macrophage polarization via upregulation of STAT3.","method":"RIP, mRNA stability assay, knockdown/overexpression, in vitro/in vivo functional assays, macrophage co-culture","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP + mRNA stability + functional assays; single lab","pmids":["37643553"],"is_preprint":false},{"year":2024,"finding":"NONO synergizes with IGF2BP3 (m6A reader) to promote exon6 skipping in DLG1 in an m6A-dependent manner in gallbladder cancer; IP/MS showed RBM14 binds NONO and interferes with NONO-mediated skipping, while IGF2BP3 disrupts the RBM14-NONO interaction.","method":"RIP-seq, mRNA-seq, IP/MS, Co-IP, alternative splicing (PSI) analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP-seq + IP/MS + Co-IP; single lab with multiple methods","pmids":["38341127"],"is_preprint":false},{"year":2023,"finding":"Berberine promotes TRIM21-mediated ubiquitination of IGF2BP3 (Co-IP), reducing its stability; this inhibits IGF2BP3-mediated stabilization of CDK4/CCND1 mRNA (RIP assay) and promotes G1/S phase arrest in colorectal cancer.","method":"Co-immunoprecipitation, RIP assay, CETSA, DARTS, in vivo mouse model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP + RIP + in vivo model; single lab","pmids":["36822301"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 enhances the stability and expression of MDM2 mRNA through m6A-dependent binding (MeRIP and RIP assays), promoting AML cell proliferation and ferroptosis resistance; Licochalcone A suppresses this axis affecting the MDM2/p53 pathway.","method":"MeRIP assay, RIP assay, actinomycin D mRNA stability, xenograft model, ferroptosis assays","journal":"Annals of hematology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MeRIP + RIP + stability assay; single lab","pmids":["39264435"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 enhances DDX21 mRNA stability in an m6A-dependent manner (MeRIP + RIP + luciferase reporter) in AML, driven by super-enhancer (SE)-associated IGF2BP3 expression; DDX21 recruits transcription factor YBX1 to cooperatively trigger ULK1 expression.","method":"MeRIP assay, RIP assay, luciferase reporter assay, ChIP-seq (SE identification), Co-IP, RNA-seq, in vivo AML model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP + RIP + ChIP-seq; single lab with multiple orthogonal methods","pmids":["38572589"],"is_preprint":false},{"year":2020,"finding":"IGF2BP3 activates the JAK/STAT signaling pathway in bladder cancer cells; IGF2BP3 knockdown suppressed proliferation and JAK/STAT activation, while JAK/STAT inhibitor blocked IGF2BP3 tumor-promoting activity.","method":"Overexpression/knockdown, cell proliferation, cell cycle and apoptosis assays, JAK/STAT inhibitor treatment, in vivo tumor model","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — pathway activation shown by pharmacological inhibition and expression assays but direct molecular mechanism not established; single lab","pmids":["33094561"],"is_preprint":false},{"year":2020,"finding":"IGF2BP3 increases HCC cell invasiveness by binding to the 3'UTR of ZO-1 mRNA (directly shown) and promoting formation of an miR-191-5p-induced RNA-induced silencing complex, suppressing ZO-1 expression.","method":"3'UTR binding assay, RIP, miR-191-5p inhibitor experiments, invasion assays","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP/binding assay, single lab, limited mechanistic validation","pmids":["32724385"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 promotes IGF2BP3-mediated stabilization of SERPINE1 mRNA (by RIP) in HNSCC; circPRMT5 binds to and stabilizes IGF2BP3 protein, and the IGF2BP3-SERPINE1 axis mediates circPRMT5-driven proliferation and metastasis.","method":"RIP, RNA-FISH, immunofluorescence, Western blot, rescue experiments","journal":"International journal of nanomedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP + rescue experiments confirming axis; single lab","pmids":["39931528"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 regulates SCD mRNA m6A modification via an IGF2BP3-METTL14 complex, enhancing SCD mRNA stability and promoting lipid metabolism, proliferation, and metastasis of cervical cancer.","method":"RIP, MeRIP, RNA-seq, knockdown/overexpression, in vitro/in vivo tumor assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP + MeRIP + in vivo model; single lab","pmids":["38355626"],"is_preprint":false},{"year":2023,"finding":"MYC transcriptionally activates IGF2BP3 by binding to its promoter (confirmed by luciferase assay and ChIP); IGF2BP3 then stabilizes KPNA2 mRNA via m6A modification in nasopharyngeal carcinoma.","method":"Luciferase assay, ChIP assay, MeRIP, mRNA stability assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP + luciferase + MeRIP; single lab","pmids":["35136045"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 binds and stabilizes TMBIM6 mRNA in an m6A-dependent manner (RBM15 as the writer); this stabilization was confirmed by actinomycin D mRNA decay assay and RNase MazF-based methylation site assay in laryngeal squamous cell carcinoma.","method":"RIP, MeRIP-seq, RNase MazF, actinomycin D mRNA stability assay, luciferase reporter, in vitro/in vivo assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + MeRIP + multiple mRNA stability methods; single lab","pmids":["33637103"],"is_preprint":false},{"year":2022,"finding":"circARID1A serves as a scaffold to facilitate the interaction between IGF2BP3 and SLC7A5 mRNA, increasing SLC7A5 mRNA stability; circARID1A also directly binds SLC7A5 mRNA, forming a circARID1A-IGF2BP3-SLC7A5 ternary complex promoting gastric cancer proliferation via AKT/mTOR pathway.","method":"RNA pull-down, RIP-seq, RIP, RNA-FISH/IF, in vitro/in vivo functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pull-down + RIP-seq + RIP confirming ternary complex; single lab","pmids":["35986300"],"is_preprint":false},{"year":2024,"finding":"circABCA1 forms a ternary complex with IGF2BP3 and SCARB1 mRNA to enhance SCARB1 mRNA stability, increasing cholesterol uptake; this promotes lipid raft maintenance, IGF1R/PI3K/AKT/mTOR activation, and M2 macrophage polarization in ccRCC.","method":"MS2 RNA-pulldown, RNA immunoprecipitation, RNA-FISH, lipid/cholesterol assays, co-culture system, xenograft models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pulldown + RIP + functional in vivo assays; single lab","pmids":["40684174"],"is_preprint":false}],"current_model":"IGF2BP3 is an oncofetal RNA-binding protein and m6A reader that post-transcriptionally regulates a broad array of target mRNAs by binding m6A-modified transcripts (via its KH domains) to stabilize them and enhance their translation, while also binding internal m7G modifications to promote mRNA degradation; it can be post-translationally regulated by ubiquitination (by Parkin at K213 and other E3 ligases) and lactylation, interacts with ribonucleases (XRN2, exosome) to destabilize select targets, modulates miRNA-RISC interactions to protect specific transcripts from translational repression, localizes mRNAs to cytoplasmic RNA granules for local translation in cell protrusions, and in developmental contexts stabilizes maternal mRNAs and controls P-TEFb activation by protecting 7SK RNA, collectively driving oncogenesis, metabolic reprogramming, immune evasion, and cell fate decisions."},"narrative":{"mechanistic_narrative":"IGF2BP3 is an oncofetal RNA-binding protein that acts principally as an N6-methyladenosine (m6A) reader, recognizing m6A-marked transcripts to control their stability, translation, and processing across oncogenic, metabolic, immune, and developmental programs [PMID:35197058, PMID:39198433, PMID:40328743]. Its KH domains mediate direct binding to target mRNAs, and the first KH domain carries a regulatory ubiquitination site (K213) whose modification by the E3 ligase Parkin triggers proteasomal degradation and abolishes the protein's m6A-reader oncogenic function [PMID:37877353]. The dominant output of m6A recognition is transcript stabilization: IGF2BP3 prolongs the half-life of oncogenic and metabolic mRNAs including MYC and CDK6 [PMID:26974154], CCND1 [PMID:32993738], PD-L1 [PMID:35197058], and serine-synthesis genes ATF4/PHGDH/PSAT1 [PMID:40328743], thereby driving proliferation, immune evasion, and metabolic reprogramming. The same reader activity desensitizes tumor cells to ferroptosis by stabilizing anti-ferroptotic transcripts such as NRF2, GPX4, and SLC3A2 [PMID:36030651, PMID:36457846]. Beyond stabilization, IGF2BP3 also binds internal m7G modifications and, in contrast to its m6A role, promotes degradation of m7G-marked transcripts including TP53 [PMID:39198433], and can destabilize select m6A targets through partnership with ribonucleases XRN2 and the exosome [PMID:26522719]. IGF2BP3 additionally protects specific transcripts from miRNA/RISC-mediated repression by occupying or overlapping microRNA binding sites [PMID:27210763, PMID:30797711], localizes target mRNAs to cytoplasmic RNA granules in membrane protrusions for local translation during invasion [PMID:25216519], and in development stabilizes maternal mRNAs and, with Lin28b, governs the fetal-to-adult hematopoietic switch [PMID:31221665, PMID:32127635]. Its abundance is itself heavily regulated by competing E3 ligases (HECTD4, TRIM21, MIB1-linked pathways) and by metabolic lactylation that retunes its target repertoire [PMID:35031058, PMID:36822301, PMID:39450426]. Loss-of-function in mouse and zebrafish models confirms requirements in leukemogenesis, germ-cell and maternal-to-zygotic transition control, and tissue regeneration [PMID:34321607, PMID:34214072, PMID:37188676].","teleology":[{"year":2015,"claim":"Established that IGF2BP3 does not act in isolation but couples to ribonucleases to destabilize select transcripts, an early indication that the protein controls mRNA turnover bidirectionally rather than acting only as a stabilizer.","evidence":"RIP-seq plus co-IP with XRN2 and exosome components and depletion rescue in cancer cells","pmids":["26522719"],"confidence":"High","gaps":["Did not establish whether ribonuclease recruitment depends on RNA modification status","Generality across target classes unclear"]},{"year":2016,"claim":"Defined direct oncogenic targets and an unconventional regulatory mode: IGF2BP3 stabilizes MYC/CDK6 via 3'UTR elements and shapes miRNA-RISC engagement, linking it to proliferation, survival, and invasion.","evidence":"CLIP-seq and iCLIP with knockdown/enforced expression and in vivo bone marrow and invasion assays","pmids":["26974154","27210763"],"confidence":"High","gaps":["Whether m6A drives target selection was not yet addressed","Mechanism of RISC promotion vs. protection not resolved"]},{"year":2017,"claim":"Extended IGF2BP3 function beyond mRNA to a noncoding RNA target, showing it protects 7SK RNA to restrain P-TEFb and control developmental cell-fate transitions.","evidence":"Knockdown in neonatal megakaryocyte progenitors with phenotypic and 7SK stability assays","pmids":["28481226"],"confidence":"High","gaps":["Binding determinants on 7SK not defined","Whether m6A or other marks mediate 7SK recognition unknown"]},{"year":2019,"claim":"Placed IGF2BP3 within a Lin28b partnership and autoregulatory loop that stabilizes thousands of mRNAs, explaining its role in the fetal-adult hematopoietic switch.","evidence":"Proteomics, in situ interaction analysis, scRNA-seq, and enforced co-expression in adult HSPCs","pmids":["31221665"],"confidence":"High","gaps":["Direct vs. indirect Lin28b binding interface not mapped","Relative contribution of each partner to stabilization unclear"]},{"year":2020,"claim":"Crystallized the central paradigm that IGF2BP3 is an m6A reader stabilizing modified transcripts (CCND1, VEGF), connecting modification recognition to cell cycle and angiogenesis control.","evidence":"RIP/MeRIP with cell cycle and rescue assays; parallel maternal mRNA stabilization in zebrafish mutants","pmids":["32993738","32127635"],"confidence":"Medium","gaps":["Quantitative binding affinity for m6A vs. unmodified sites not measured here","Reader activity vs. stabilizer-protein recruitment not separated"]},{"year":2021,"claim":"Genetic deletion demonstrated causal requirement in leukemia and revealed an unexpected role in pre-mRNA splicing, broadening function beyond mRNA stability.","evidence":"Igf2bp3 knockout in MLL-Af4 mouse leukemia with RNA-seq, splicing analysis, and survival","pmids":["34321607"],"confidence":"High","gaps":["Mechanism of splicing regulation not defined","Whether nuclear vs. cytoplasmic pools drive distinct outputs unresolved"]},{"year":2022,"claim":"Connected IGF2BP3 m6A reading to immune evasion and ferroptosis resistance, establishing it as a node where mRNA modification controls the tumor microenvironment and cell-death sensitivity.","evidence":"MeRIP-seq/RIP-qPCR for PD-L1 and anti-ferroptotic transcripts with xenograft and ferroptosis readouts","pmids":["35197058","36030651","36457846"],"confidence":"High","gaps":["Whether a single binding mode governs all these targets unknown","Context dependence of target selection not addressed"]},{"year":2023,"claim":"Identified post-translational control of IGF2BP3 abundance, showing Parkin ubiquitinates K213 in KH1 to trigger degradation and that diverse circRNAs shield it from competing E3 ligases, linking protein stability to its oncogenic activity.","evidence":"In vitro/in vivo ubiquitination assays, MS site mapping, functional mutagenesis, and circRNA pull-down/Co-IP with HECTD4 and TRIM25","pmids":["37877353","35031058","37340423"],"confidence":"High","gaps":["Full E3 ligase repertoire and deubiquitinases incomplete","How modification at K213 alters RNA binding structurally not shown"]},{"year":2024,"claim":"Revealed modification-specific bifunctionality and metabolic input: IGF2BP3 reads internal m7G to degrade transcripts including TP53, while glycolysis-driven lactylation retunes its target capture in metabolic reprogramming.","evidence":"In vitro binding, dCas13b-guided site-specific m7G targeting, half-life assays, and lactylation modification/RIP assays","pmids":["39198433","39450426"],"confidence":"High","gaps":["Structural basis for opposing m6A vs. m7G outcomes unknown","How lactylation alters domain function not defined"]},{"year":2024,"claim":"Demonstrated that IGF2BP3 sustains serine and other metabolic programs through m6A stabilization, providing a therapeutic vulnerability via combined silencing and dietary restriction.","evidence":"CRISPR screen, RIP, mRNA stability assays, and dietary restriction in AML mouse models","pmids":["40328743"],"confidence":"High","gaps":["Selectivity for metabolic over other targets not mechanistically explained","Normal-tissue dependence beyond hematopoiesis not mapped"]},{"year":null,"claim":"How a single reader discriminates among m6A (stabilizing), m7G (destabilizing), and ribonuclease-coupled fates on different transcripts, and what structural or PTM state dictates each outcome, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking domain occupancy to opposing transcript fates","Rules governing partner (XRN2, exosome, HuR, stabilizer) selection unknown","Quantitative competition between stabilizing and degradative modes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,11,18,26]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,18,22]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,11,18,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,26,53]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,42]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,9,10]}],"complexes":[],"partners":["LIN28B","XRN2","ILF3","PTBP1","METTL14","PARK2","TRIM25","NONO"],"other_free_text":[]}},"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 Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000136231","cell_line_id":"CID001516","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"IGF2BP1","stoichiometry":10.0},{"gene":"NDUFA3","stoichiometry":4.0},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001516","total_profiled":1310},"omim":[{"mim_id":"608289","title":"INSULIN-LIKE GROWTH FACTOR 2 mRNA-BINDING PROTEIN 2; IGF2BP2","url":"https://www.omim.org/entry/608289"},{"mim_id":"608288","title":"INSULIN-LIKE GROWTH FACTOR 2 mRNA-BINDING PROTEIN 1; IGF2BP1","url":"https://www.omim.org/entry/608288"},{"mim_id":"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 and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936.","date":"2003","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/14671650","citation_count":2521,"is_preprint":false},{"pmid":"35197058","id":"PMC_35197058","title":"METTL3/IGF2BP3 axis inhibits tumor immune surveillance by upregulating N6-methyladenosine modification of PD-L1 mRNA in breast cancer.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35197058","citation_count":352,"is_preprint":false},{"pmid":"35031058","id":"PMC_35031058","title":"EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35031058","citation_count":263,"is_preprint":false},{"pmid":"25068994","id":"PMC_25068994","title":"The role of the oncofetal IGF2 mRNA-binding protein 3 (IGF2BP3) in cancer.","date":"2014","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/25068994","citation_count":238,"is_preprint":false},{"pmid":"32993738","id":"PMC_32993738","title":"RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32993738","citation_count":230,"is_preprint":false},{"pmid":"17170731","id":"PMC_17170731","title":"Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. 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remodeled focal adhesion junctions.\",\n      \"method\": \"iCLIP (individual nucleotide resolution crosslinking immunoprecipitation), genome-wide approaches, loss-of-function assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genome-wide iCLIP with functional validation (invasion, focal adhesion remodeling), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27210763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF2BP3 directly targets oncogenic transcripts MYC and CDK6 via elements within 3' UTRs to stabilize them, promoting hematopoietic progenitor proliferation and survival; enforced IGF2BP3 expression in mice enhanced Myc and Cdk6 expression in bone marrow.\",\n      \"method\": \"Cross-link immunoprecipitation and high-throughput sequencing (CLIP-seq), knockdown/enforced expression in murine BM cells, in vivo mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CLIP-seq with in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26974154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF2BP3 destabilizes EIF4E-BP2 and MEIS3 mRNAs through interaction with ribonucleases XRN2 and exosome components (co-IP), thereby facilitating eIF4E-mediated translational activation and promoting cell proliferation.\",\n      \"method\": \"RNA immunoprecipitation followed by massively parallel sequencing, co-immunoprecipitation with XRN2 and exosome components, IGF2BP3 depletion rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying ribonuclease partners, sequencing-based target identification, functional rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26522719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGF2BP3 and IGF2BP3-bound transcripts (ARF6 and ARHGEF4) localize to cytoplasmic RNA granules accumulating in membrane protrusions of pancreatic cancer cells, where they are preferentially translated to induce further protrusion formation, promoting cell invasiveness and tumor metastasis.\",\n      \"method\": \"Subcellular fractionation/localization imaging, translation assays in membrane protrusions, in vivo metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — localization tied to functional consequence (invasion/metastasis), single lab with multiple methods\",\n      \"pmids\": [\"25216519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGF2BP3 (neonatal-specific expression) prevents destabilization of nuclear RNA 7SK, thereby blocking P-TEFb activation in neonatal megakaryocytes and restricting adult-type megakaryocyte morphogenesis; IGF2BP3 knockdown conferred adult-type phenotypic and molecular features on neonatal megakaryocytes.\",\n      \"method\": \"Knockdown in neonatal progenitors, phenotypic assays (polyploidization, proplatelet formation), molecular analysis of 7SK RNA stability\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and mechanistic link to 7SK/P-TEFb, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"28481226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lin28b directly interacts with IGF2BP3 (shown by proteomics and in situ analyses), and together they stabilize thousands of mRNAs including Pax5 and Arid3a by binding at the same sites; IGF2BP3 mRNA itself is a target, forming an autoregulatory loop that mediates fetal-adult hematopoietic switch.\",\n      \"method\": \"Proteomics, in situ interaction analyses, single-cell RNA sequencing, enforced co-expression in adult HSPCs\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics + in situ validation + functional co-expression, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31221665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF2BP3 regulates a posttranscriptional operon in MLL-Af4 leukemia, controlling steady-state mRNA levels of Hoxa locus genes and Ras signaling pathway transcripts, and unexpectedly also regulates pre-mRNA splicing; Igf2bp3 deletion significantly increases survival of MLL-Af4 leukemia mice.\",\n      \"method\": \"Genetic deletion (Igf2bp3 knockout) in mouse leukemia model, RNA-seq, splicing analysis, in vivo survival assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined in vivo phenotype, RNA-seq, splicing analysis; single lab with multiple orthogonal methods and robust in vivo data\",\n      \"pmids\": [\"34321607\"],\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, D3 and G1 mRNAs and protect them from translational repression induced by miRNA-dependent recruitment of AGO2/GW182 complex; this regulation depends on nuclear localization of IMP-3.\",\n      \"method\": \"Knockdown experiments, polyribosome association assays, co-immunoprecipitation with AGO2/GW182\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional interaction with RISC components shown, nuclear localization requirement demonstrated, single lab\",\n      \"pmids\": [\"27840950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGF2BP3 competitively occupies the miR-3614-3p binding site on TRIM25 mRNA 3'UTR and inhibits miR-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation and promoting breast cancer cell proliferation.\",\n      \"method\": \"Luciferase activation assays, RNA immunoprecipitation (RIP), biotin pull-down assays, in vitro and in vivo loss/gain-of-function\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP and pulldown with functional validation, single lab, multiple methods\",\n      \"pmids\": [\"30797711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, Igf2bp3 maintains maternal mRNA stability prior to the maternal-to-zygotic transition; depletion of maternal igf2bp3 destabilizes maternal mRNAs and causes abnormal cytoskeleton organization and cell division, while overexpression enhances stability of target maternal mRNAs.\",\n      \"method\": \"Maternal igf2bp3 mutant zebrafish, mRNA stability assays, GO analysis, overexpression experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic mutant with defined developmental phenotype, mRNA stability assays, overexpression rescue; multiple orthogonal approaches\",\n      \"pmids\": [\"32127635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, Igf2bp3 loss leads to expanded yolk syncytial layer, reduced germline RNA expression, translational de-regulation of a Nodal reporter during mid-blastula transition, and defects in primordial germ cell behavior and germ cell death; adult igf2bp3 mutants show strong male bias.\",\n      \"method\": \"Igf2bp3 maternal/zygotic mutants, Nodal reporter assay, RNA/PGC analysis, adult phenotype assessment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic mutant with multiple defined phenotypes at molecular and cellular level, translational reporter assay\",\n      \"pmids\": [\"34214072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A modification of PD-L1 mRNA is read by IGF2BP3, which stabilizes PD-L1 mRNA; IGF2BP3 knockdown reduced PD-L1 mRNA stability and enhanced anti-tumor T cell activity in vitro and in vivo.\",\n      \"method\": \"MeRIP-seq, MeRIP-qPCR, RIP-qPCR, m6A quantification, xenograft mouse models, knockdown experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq, RIP-qPCR, and in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35197058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF2BP3 acts as an m6A reader that binds to m6A-modified CCND1 mRNA in its CDS region to regulate mRNA stability, and similarly reads m6A modification on VEGF mRNA to regulate its stability; knockdown of IGF2BP3 repressed S-phase entry and angiogenesis in colon cancer.\",\n      \"method\": \"RNA immunoprecipitation (RIP), m6A RNA immunoprecipitation (MeRIP), cell cycle flow cytometry, rescue experiments with CCND1 overexpression\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP and MeRIP with functional rescue, single lab\",\n      \"pmids\": [\"32993738\"],\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; IGF2BP3 knockdown suppressed AML cell survival, proliferation, and leukemic capacity in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation, m6A modification assays, knockdown in AML cell lines, in vivo leukemia models\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP with m6A assay and in vivo validation, single lab\",\n      \"pmids\": [\"35217832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Parkin (E3 ubiquitin ligase) directly interacts with IGF2BP3 and ubiquitinates it at K213 in the first KH domain, leading to proteasomal degradation; K213 mutation abolishes IGF2BP3's oncogenic function as an m6A reader and inactivates PI3K and MAPK signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vivo and in vitro ubiquitination assays, mass spectrometry (ubiquitination site identification), RNA immunoprecipitation, xenograft mouse model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro/in vivo ubiquitination assay, MS-identified modification site, functional mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"37877353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circNEIL3 (and other circRNAs) stabilize IGF2BP3 protein by preventing HECTD4-mediated ubiquitination; this protects IGF2BP3 from proteasomal degradation in glioma cells.\",\n      \"method\": \"RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), co-immunoprecipitation assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pulldown, MS, Co-IP showing interaction with HECTD4; single lab\",\n      \"pmids\": [\"35031058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circNFATC3 binds to IGF2BP3 and prevents TRIM25-mediated ubiquitination, thereby enhancing IGF2BP3 protein stability and enabling it to promote CCND1 mRNA stability in gastric cancer cells.\",\n      \"method\": \"RIP, RNA-FISH/IF, IP, rescue experiments, co-immunoprecipitation\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and RIP showing mechanistic interaction, single lab\",\n      \"pmids\": [\"37340423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 enhances translational efficiency of COPS7B mRNA to promote colorectal cancer growth and metastasis; COPS7B interacts with ribosomes to facilitate ribosome biogenesis and mRNA translation initiation.\",\n      \"method\": \"RIP-seq, ribosome-protected mRNA analysis (ribosome profiling), proteomics, functional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome profiling combined with proteomics and RIP-seq; single lab\",\n      \"pmids\": [\"37560971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 preferentially binds internal mRNA m7G modifications and, unlike its m6A-binding activity which stabilizes transcripts, IGF2BP3-m7G interaction promotes degradation of m7G-modified target transcripts including TP53 in cancer cells.\",\n      \"method\": \"In vitro binding assays, m7G modification assays, IGF2BP3 knockdown/modulation, dCas13b-guided site-specific m7G targeting, mRNA half-life measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding, site-specific m7G targeting, mRNA stability assays with functional consequence; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39198433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lysine lactylation of IGF2BP3 (driven by increased glycolysis/lactate accumulation) is required for capturing PCK2 and NRF2 mRNAs, enhancing their expression and reprogramming serine metabolism; this lactylated IGF2BP3-PCK2-SAM-m6A loop promotes lenvatinib resistance in HCC.\",\n      \"method\": \"Lactylation modification assays, RIP assays, in vitro and in vivo lenvatinib-resistant models, siRNA liposome delivery\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — novel PTM (lactylation) identified with functional consequence, RIP assays; single lab\",\n      \"pmids\": [\"39450426\"],\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 COX6B2 mRNA stability, promoting oxidative phosphorylation and EGFR-TKI resistance in non-small cell lung cancer.\",\n      \"method\": \"RIP, MeRIP, mRNA stability assays, in vitro/in vivo EGFR-TKI resistance models, patient-derived xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + MeRIP + functional rescue in patient-derived xenograft; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37061993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 binds m6A-modified MCM5 mRNA to prolong its stability, upregulating MCM5 protein which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizing NICD1 and activating Notch signaling to promote partial EMT in lung adenocarcinoma.\",\n      \"method\": \"MeRIP-seq, RIP, mRNA stability assay, co-immunoprecipitation, in vitro and in vivo functional assays, clinical LUAD specimen correlation\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP, RIP, and mechanistic Co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37171793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 binds to and stabilizes m6A-modified NRF2 mRNA (identified by RIP and RNA pulldown), preventing ferroptosis in hepatocellular carcinoma; IGF2BP3 knockdown promoted ferroptosis and sensitized HCC cells to sorafenib.\",\n      \"method\": \"RIP, RNA pulldown, m6A reader activity assay, ferroptosis markers (ROS, Fe2+, MDA), in vivo experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP and pulldown with functional ferroptosis readouts; single lab\",\n      \"pmids\": [\"36030651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 binds to and stabilizes m6A-modified mRNAs of anti-ferroptotic factors (GPX4, SLC3A2, ACSL3, FTH1) in an m6A reading domain-dependent manner in lung adenocarcinoma, desensitizing cells to ferroptosis.\",\n      \"method\": \"RIP, MeRIP, mRNA stability assay, IGF2BP3 overexpression, correlation in clinical LUAD specimens\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP and MeRIP with functional validation, single lab\",\n      \"pmids\": [\"36457846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 stabilizes MMP3 mRNA through interaction with N6-methyladenosine modification; IGF2BP3 expression is upregulated after cardiac injury and both gain- and loss-of-function analyses show it regulates cardiomyocyte proliferation in vitro and in vivo, promoting cardiac regeneration after myocardial infarction.\",\n      \"method\": \"RIP, m6A modification assays, gain/loss-of-function in mouse myocardial infarction model, cardiomyocyte proliferation assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP with m6A interaction shown and in vivo cardiac model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37188676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 stabilizes GLI2 mRNA by targeting its m6A site; stabilized GLI2 then transcriptionally promotes SYVN1, which ubiquitinates and degrades PPARα, inhibiting PPARα-mediated autophagy and exacerbating liver injury in sepsis.\",\n      \"method\": \"RIP, m6A assays, ChIP-qPCR, knockdown experiments in vitro and in cecal ligation and puncture mouse model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP + ChIP + in vivo model; single lab with multiple methods\",\n      \"pmids\": [\"38799573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 recognizes m6A on mRNAs of key serine synthesis pathway genes (ATF4, PHGDH, PSAT1), stabilizing these transcripts to sustain serine production; IGF2BP3 silencing combined with dietary serine/glycine restriction potently inhibits AML in vitro and in vivo while sparing normal hematopoiesis.\",\n      \"method\": \"CRISPR/Cas9 screen, RIP, mRNA stability assays, dietary restriction mouse models, AML in vivo experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen + RIP + dietary restriction in vivo; multiple orthogonal methods with in vivo validation\",\n      \"pmids\": [\"40328743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 promotes CAMK1 mRNA stability via m6A modification (MeRIP and RIP assays); IGF2BP3-CAMK1 axis inhibits mitochondrial fission to alleviate diabetic nephropathy progression in vitro and in vivo.\",\n      \"method\": \"MeRIP assay, RIP assay, dual-luciferase reporter, actinomycin D mRNA stability assay, CAMK1 conditional KO mice, STZ diabetic mouse model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP + RIP + conditional KO mouse model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38216068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 recognizes m6A modification on HIF1A mRNA, increasing HIF1A RNA stability and expression; stabilized HIF1A activates RhoA/YAP signaling to promote hepatocyte reprogramming in acute-on-chronic liver failure.\",\n      \"method\": \"m6A dot assay, m6A-antibody precipitation PCR, overexpression and knockdown in HepG2/Hep3B cells, EdU staining, sphere formation assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — m6A RIP with functional downstream validation; single lab\",\n      \"pmids\": [\"37257765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP-mediated m6A modification of ULK1 mRNA is recognized and stabilized by IGF2BP3 in an m6A-dependent manner, leading to elevated ULK1 expression and enhanced mitophagy in epithelial ovarian cancer.\",\n      \"method\": \"MeRIP assay, RIP assay, knockdown/overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MeRIP + RIP assays with functional validation; single lab\",\n      \"pmids\": [\"38286802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 enhances mRNA stability of HMGB1 by binding to its mRNA (RIP assay), promoting inflammation and bladder cancer progression; pharmacological inhibition of HMGB1 reverses IGF2BP3 overexpression-induced cancer-promoting effects.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assays, proliferation/migration/invasion assays, xenograft model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP with mRNA stability assay and in vivo model; 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 repressing MSC adipogenesis; IGF2BP3 overexpression via AAV in adipose tissue reduced body weight and improved insulin resistance in high-fat diet mice.\",\n      \"method\": \"RIP, m6A interaction assay, mRNA half-life assay, MSC differentiation assays, AAV-mediated overexpression in mice\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + mRNA stability + in vivo AAV model; single lab with multiple methods\",\n      \"pmids\": [\"38196046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 enhances RRM2 mRNA stability by reading its m6A modification (MeRIP assay), promoting HCC cell malignant behaviors and M2 macrophage polarization by suppressing ferroptosis; FOXM1 is an upstream transcriptional activator of IGF2BP3 (ChIP + dual-luciferase).\",\n      \"method\": \"MeRIP, RIP, ChIP, dual-luciferase reporter, Co-IP, ferroptosis assays (MDA, GSH, ROS, lipid ROS), flow cytometry, xenograft model\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP + RIP + ChIP + in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39630361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 promotes m6A-dependent stabilization of EGFR mRNA in cooperation with METTL14, activating the EGFR pathway and mediating cetuximab resistance in colorectal cancer.\",\n      \"method\": \"MeRIP, RIP, mRNA stability assay, co-immunoprecipitation with METTL14, functional assays, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MeRIP + RIP + Co-IP with writer protein; single lab\",\n      \"pmids\": [\"37658049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 binds to and destabilizes m6A-methylated SLIT2 mRNA in triple-negative breast cancer, impairing SLIT2/ROBO1 signaling and triggering activation of PI3K/AKT and MEK/ERK pathways to promote metastasis.\",\n      \"method\": \"RIP, MeRIP, mRNA stability assay, in vivo metastasis model, functional migration/invasion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP and MeRIP with in vivo validation; single lab\",\n      \"pmids\": [\"36250924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 regulates NFAT1 mRNA stability and translation in an m6A-dependent manner; NFAT1 induced by IGF2BP3 acts as a transcription factor to suppress IRF1 expression, inactivating interferon signaling and promoting gastric cancer progression.\",\n      \"method\": \"Ribo-seq, RNA-seq, m6A-seq, gain/loss-of-function experiments, mRNA stability assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics (Ribo-seq + RNA-seq + m6A-seq) with functional validation; single lab\",\n      \"pmids\": [\"38448411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In neuroblastoma, IGF2BP3 and MYCN form a positive feedback loop: IGF2BP3 stabilizes MYCN mRNA via m6A modification, while MYCN acts as a transcription factor that directly promotes IGF2BP3 expression.\",\n      \"method\": \"RIP, MeRIP, ChIP assays, knockdown/overexpression in vitro and in vivo\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP + MeRIP + ChIP; single lab\",\n      \"pmids\": [\"37156775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circRARS binds to KH1-KH2 domains of IGF2BP3 (12-nt sequence GUCUUCCAGCAA identified as binding site), enhancing m6A modification recognition; the IGF2BP3/circRARS complex stabilizes target mRNAs (CAPN15, CD44, HMGA2, TNRC6A, ZMIZ2) by recruiting stabilizer proteins HuR, Matrin3, and pAbPC1.\",\n      \"method\": \"RIP, RNA pull-down, domain mapping, mRNA stability assays, co-immunoprecipitation, in vitro and in vivo experiments\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain-level binding site identified, RIP with stabilizer protein recruitment; single lab\",\n      \"pmids\": [\"38073586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP-mediated m6A modification of GBE1 mRNA is stabilized by IGF2BP3 through RIP-confirmed interaction; WTAP/IGF2BP3 axis increases GBE1 mRNA stability and expression to promote pancreatic cancer cell proliferation and stemness via c-Myc.\",\n      \"method\": \"RIP assay, RNA stability experiments, Western blot, functional assays, subcutaneous/orthotopic mouse models\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP + stability assay + in vivo model; single lab\",\n      \"pmids\": [\"38961325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 upregulation in glioma enhances expression of E3 ubiquitin ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway, resulting in increased m6A-mediated CSF3 release and NET formation (NETosis); BET inhibitor reduces IGF2BP3 expression via BRD4/CDK9/RPB-1.\",\n      \"method\": \"IGF2BP3 overexpression/knockdown, ubiquitin-proteasome pathway assays, m6A assays, in vivo glioma models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic pathway linking IGF2BP3 to FTO/m6A/NETosis demonstrated; single lab\",\n      \"pmids\": [\"38167409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP-mediated m6A modification of EGR1 mRNA requires IGF2BP3 as a reader for recognition and stability; loss of WTAP decreases m6A on EGR1 mRNA, reducing IGF2BP3 binding and EGR1 mRNA stability, leading to decreased PTEN expression and promoting endometrial cancer stem cell traits.\",\n      \"method\": \"m6A modification assays, RIP, Western blot, gain-of-function rescue experiments in vivo\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic m6A reader function demonstrated with in vivo rescue; single lab\",\n      \"pmids\": [\"39044249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 deficiency in hepatic stellate cells reduces m6A content in Jagged1 (Jag1) mRNA, decreasing Notch/Hes1 signaling and GPX4 levels, thereby promoting ferroptosis in HSCs and reducing liver fibrosis.\",\n      \"method\": \"IGF2BP3 knockout mouse, multi-omics analysis, m6A quantification of Jag1, in vitro and in vivo ferroptosis assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse + multi-omics + ferroptosis assays; single lab with multiple methods\",\n      \"pmids\": [\"39113232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 promotes LDHA mRNA stability via m6A binding (RIP confirmed), increasing lactate accumulation and impairing CD8+ T cell anti-tumor immunity in gastric cancer.\",\n      \"method\": \"RIP, mRNA stability assay, co-culture system with CD8+ T cells, functional assays\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP with functional immune co-culture readout; single lab\",\n      \"pmids\": [\"39397122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 promotes m6A-dependent stabilization of SENP1 mRNA (3'UTR binding confirmed by MERIP-qPCR and RIP-qPCR), enhancing SENP1 expression which de-SUMOylates HDAC2 to activate EGFR transcription and the AKT pathway in AML.\",\n      \"method\": \"MERIP-qPCR, RIP-qPCR, CO-IP, RNA pulldown, dual-luciferase reporter, ChIP-qPCR\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MeRIP + RIP + Co-IP identifying mechanistic axis; single lab\",\n      \"pmids\": [\"38822351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 binds to m6A-modified RASGRF1 mRNA to stabilize it, activating mTORC1 signaling in RA fibroblast-like synoviocytes; IGF2BP3 knockout in mice ameliorated arthritis joint injury and reduced inflammatory infiltration.\",\n      \"method\": \"RIP, MeRIP, IGF2BP3 KO mouse arthritis model (K/BxN serum transfer), transfection experiments\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + MeRIP + KO mouse model; single lab with multiple methods\",\n      \"pmids\": [\"40355406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP3 promotes m6A-dependent stabilization of CLDN4 mRNA in gallbladder cancer, activating NF-κB signaling; overexpression of IGF2BP3 also promotes M2 macrophage polarization via upregulation of STAT3.\",\n      \"method\": \"RIP, mRNA stability assay, knockdown/overexpression, in vitro/in vivo functional assays, macrophage co-culture\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP + mRNA stability + functional assays; single lab\",\n      \"pmids\": [\"37643553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NONO synergizes with IGF2BP3 (m6A reader) to promote exon6 skipping in DLG1 in an m6A-dependent manner in gallbladder cancer; IP/MS showed RBM14 binds NONO and interferes with NONO-mediated skipping, while IGF2BP3 disrupts the RBM14-NONO interaction.\",\n      \"method\": \"RIP-seq, mRNA-seq, IP/MS, Co-IP, alternative splicing (PSI) analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP-seq + IP/MS + Co-IP; single lab with multiple methods\",\n      \"pmids\": [\"38341127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Berberine promotes TRIM21-mediated ubiquitination of IGF2BP3 (Co-IP), reducing its stability; this inhibits IGF2BP3-mediated stabilization of CDK4/CCND1 mRNA (RIP assay) and promotes G1/S phase arrest in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, RIP assay, CETSA, DARTS, in vivo mouse model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP + RIP + in vivo model; single lab\",\n      \"pmids\": [\"36822301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 enhances the stability and expression of MDM2 mRNA through m6A-dependent binding (MeRIP and RIP assays), promoting AML cell proliferation and ferroptosis resistance; Licochalcone A suppresses this axis affecting the MDM2/p53 pathway.\",\n      \"method\": \"MeRIP assay, RIP assay, actinomycin D mRNA stability, xenograft model, ferroptosis assays\",\n      \"journal\": \"Annals of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MeRIP + RIP + stability assay; single lab\",\n      \"pmids\": [\"39264435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 enhances DDX21 mRNA stability in an m6A-dependent manner (MeRIP + RIP + luciferase reporter) in AML, driven by super-enhancer (SE)-associated IGF2BP3 expression; DDX21 recruits transcription factor YBX1 to cooperatively trigger ULK1 expression.\",\n      \"method\": \"MeRIP assay, RIP assay, luciferase reporter assay, ChIP-seq (SE identification), Co-IP, RNA-seq, in vivo AML model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP + RIP + ChIP-seq; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38572589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF2BP3 activates the JAK/STAT signaling pathway in bladder cancer cells; IGF2BP3 knockdown suppressed proliferation and JAK/STAT activation, while JAK/STAT inhibitor blocked IGF2BP3 tumor-promoting activity.\",\n      \"method\": \"Overexpression/knockdown, cell proliferation, cell cycle and apoptosis assays, JAK/STAT inhibitor treatment, in vivo tumor model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway activation shown by pharmacological inhibition and expression assays but direct molecular mechanism not established; single lab\",\n      \"pmids\": [\"33094561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF2BP3 increases HCC cell invasiveness by binding to the 3'UTR of ZO-1 mRNA (directly shown) and promoting formation of an miR-191-5p-induced RNA-induced silencing complex, suppressing ZO-1 expression.\",\n      \"method\": \"3'UTR binding assay, RIP, miR-191-5p inhibitor experiments, invasion assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP/binding assay, single lab, limited mechanistic validation\",\n      \"pmids\": [\"32724385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 promotes IGF2BP3-mediated stabilization of SERPINE1 mRNA (by RIP) in HNSCC; circPRMT5 binds to and stabilizes IGF2BP3 protein, and the IGF2BP3-SERPINE1 axis mediates circPRMT5-driven proliferation and metastasis.\",\n      \"method\": \"RIP, RNA-FISH, immunofluorescence, Western blot, rescue experiments\",\n      \"journal\": \"International journal of nanomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP + rescue experiments confirming axis; single lab\",\n      \"pmids\": [\"39931528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 regulates SCD mRNA m6A modification via an IGF2BP3-METTL14 complex, enhancing SCD mRNA stability and promoting lipid metabolism, proliferation, and metastasis of cervical cancer.\",\n      \"method\": \"RIP, MeRIP, RNA-seq, knockdown/overexpression, in vitro/in vivo tumor assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP + MeRIP + in vivo model; single lab\",\n      \"pmids\": [\"38355626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYC transcriptionally activates IGF2BP3 by binding to its promoter (confirmed by luciferase assay and ChIP); IGF2BP3 then stabilizes KPNA2 mRNA via m6A modification in nasopharyngeal carcinoma.\",\n      \"method\": \"Luciferase assay, ChIP assay, MeRIP, mRNA stability assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP + luciferase + MeRIP; single lab\",\n      \"pmids\": [\"35136045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 binds and stabilizes TMBIM6 mRNA in an m6A-dependent manner (RBM15 as the writer); this stabilization was confirmed by actinomycin D mRNA decay assay and RNase MazF-based methylation site assay in laryngeal squamous cell carcinoma.\",\n      \"method\": \"RIP, MeRIP-seq, RNase MazF, actinomycin D mRNA stability assay, luciferase reporter, in vitro/in vivo assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + MeRIP + multiple mRNA stability methods; single lab\",\n      \"pmids\": [\"33637103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circARID1A serves as a scaffold to facilitate the interaction between IGF2BP3 and SLC7A5 mRNA, increasing SLC7A5 mRNA stability; circARID1A also directly binds SLC7A5 mRNA, forming a circARID1A-IGF2BP3-SLC7A5 ternary complex promoting gastric cancer proliferation via AKT/mTOR pathway.\",\n      \"method\": \"RNA pull-down, RIP-seq, RIP, RNA-FISH/IF, in vitro/in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pull-down + RIP-seq + RIP confirming ternary complex; single lab\",\n      \"pmids\": [\"35986300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circABCA1 forms a ternary complex with IGF2BP3 and SCARB1 mRNA to enhance SCARB1 mRNA stability, increasing cholesterol uptake; this promotes lipid raft maintenance, IGF1R/PI3K/AKT/mTOR activation, and M2 macrophage polarization in ccRCC.\",\n      \"method\": \"MS2 RNA-pulldown, RNA immunoprecipitation, RNA-FISH, lipid/cholesterol assays, co-culture system, xenograft models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pulldown + RIP + functional in vivo assays; single lab\",\n      \"pmids\": [\"40684174\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2BP3 is an oncofetal RNA-binding protein and m6A reader that post-transcriptionally regulates a broad array of target mRNAs by binding m6A-modified transcripts (via its KH domains) to stabilize them and enhance their translation, while also binding internal m7G modifications to promote mRNA degradation; it can be post-translationally regulated by ubiquitination (by Parkin at K213 and other E3 ligases) and lactylation, interacts with ribonucleases (XRN2, exosome) to destabilize select targets, modulates miRNA-RISC interactions to protect specific transcripts from translational repression, localizes mRNAs to cytoplasmic RNA granules for local translation in cell protrusions, and in developmental contexts stabilizes maternal mRNAs and controls P-TEFb activation by protecting 7SK RNA, collectively driving oncogenesis, metabolic reprogramming, immune evasion, and cell fate decisions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IGF2BP3 is an oncofetal RNA-binding protein that acts principally as an N6-methyladenosine (m6A) reader, recognizing m6A-marked transcripts to control their stability, translation, and processing across oncogenic, metabolic, immune, and developmental programs [#11, #18, #26]. Its KH domains mediate direct binding to target mRNAs, and the first KH domain carries a regulatory ubiquitination site (K213) whose modification by the E3 ligase Parkin triggers proteasomal degradation and abolishes the protein's m6A-reader oncogenic function [#14]. The dominant output of m6A recognition is transcript stabilization: IGF2BP3 prolongs the half-life of oncogenic and metabolic mRNAs including MYC and CDK6 [#1], CCND1 [#12], PD-L1 [#11], and serine-synthesis genes ATF4/PHGDH/PSAT1 [#26], thereby driving proliferation, immune evasion, and metabolic reprogramming. The same reader activity desensitizes tumor cells to ferroptosis by stabilizing anti-ferroptotic transcripts such as NRF2, GPX4, and SLC3A2 [#22, #23]. Beyond stabilization, IGF2BP3 also binds internal m7G modifications and, in contrast to its m6A role, promotes degradation of m7G-marked transcripts including TP53 [#18], and can destabilize select m6A targets through partnership with ribonucleases XRN2 and the exosome [#2]. IGF2BP3 additionally protects specific transcripts from miRNA/RISC-mediated repression by occupying or overlapping microRNA binding sites [#0, #8], localizes target mRNAs to cytoplasmic RNA granules in membrane protrusions for local translation during invasion [#3], and in development stabilizes maternal mRNAs and, with Lin28b, governs the fetal-to-adult hematopoietic switch [#5, #9]. Its abundance is itself heavily regulated by competing E3 ligases (HECTD4, TRIM21, MIB1-linked pathways) and by metabolic lactylation that retunes its target repertoire [#15, #47, #19]. Loss-of-function in mouse and zebrafish models confirms requirements in leukemogenesis, germ-cell and maternal-to-zygotic transition control, and tissue regeneration [#6, #10, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that IGF2BP3 does not act in isolation but couples to ribonucleases to destabilize select transcripts, an early indication that the protein controls mRNA turnover bidirectionally rather than acting only as a stabilizer.\",\n      \"evidence\": \"RIP-seq plus co-IP with XRN2 and exosome components and depletion rescue in cancer cells\",\n      \"pmids\": [\"26522719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether ribonuclease recruitment depends on RNA modification status\", \"Generality across target classes unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined direct oncogenic targets and an unconventional regulatory mode: IGF2BP3 stabilizes MYC/CDK6 via 3'UTR elements and shapes miRNA-RISC engagement, linking it to proliferation, survival, and invasion.\",\n      \"evidence\": \"CLIP-seq and iCLIP with knockdown/enforced expression and in vivo bone marrow and invasion assays\",\n      \"pmids\": [\"26974154\", \"27210763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether m6A drives target selection was not yet addressed\", \"Mechanism of RISC promotion vs. protection not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended IGF2BP3 function beyond mRNA to a noncoding RNA target, showing it protects 7SK RNA to restrain P-TEFb and control developmental cell-fate transitions.\",\n      \"evidence\": \"Knockdown in neonatal megakaryocyte progenitors with phenotypic and 7SK stability assays\",\n      \"pmids\": [\"28481226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding determinants on 7SK not defined\", \"Whether m6A or other marks mediate 7SK recognition unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed IGF2BP3 within a Lin28b partnership and autoregulatory loop that stabilizes thousands of mRNAs, explaining its role in the fetal-adult hematopoietic switch.\",\n      \"evidence\": \"Proteomics, in situ interaction analysis, scRNA-seq, and enforced co-expression in adult HSPCs\",\n      \"pmids\": [\"31221665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect Lin28b binding interface not mapped\", \"Relative contribution of each partner to stabilization unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Crystallized the central paradigm that IGF2BP3 is an m6A reader stabilizing modified transcripts (CCND1, VEGF), connecting modification recognition to cell cycle and angiogenesis control.\",\n      \"evidence\": \"RIP/MeRIP with cell cycle and rescue assays; parallel maternal mRNA stabilization in zebrafish mutants\",\n      \"pmids\": [\"32993738\", \"32127635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative binding affinity for m6A vs. unmodified sites not measured here\", \"Reader activity vs. stabilizer-protein recruitment not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic deletion demonstrated causal requirement in leukemia and revealed an unexpected role in pre-mRNA splicing, broadening function beyond mRNA stability.\",\n      \"evidence\": \"Igf2bp3 knockout in MLL-Af4 mouse leukemia with RNA-seq, splicing analysis, and survival\",\n      \"pmids\": [\"34321607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of splicing regulation not defined\", \"Whether nuclear vs. cytoplasmic pools drive distinct outputs unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected IGF2BP3 m6A reading to immune evasion and ferroptosis resistance, establishing it as a node where mRNA modification controls the tumor microenvironment and cell-death sensitivity.\",\n      \"evidence\": \"MeRIP-seq/RIP-qPCR for PD-L1 and anti-ferroptotic transcripts with xenograft and ferroptosis readouts\",\n      \"pmids\": [\"35197058\", \"36030651\", \"36457846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a single binding mode governs all these targets unknown\", \"Context dependence of target selection not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-translational control of IGF2BP3 abundance, showing Parkin ubiquitinates K213 in KH1 to trigger degradation and that diverse circRNAs shield it from competing E3 ligases, linking protein stability to its oncogenic activity.\",\n      \"evidence\": \"In vitro/in vivo ubiquitination assays, MS site mapping, functional mutagenesis, and circRNA pull-down/Co-IP with HECTD4 and TRIM25\",\n      \"pmids\": [\"37877353\", \"35031058\", \"37340423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full E3 ligase repertoire and deubiquitinases incomplete\", \"How modification at K213 alters RNA binding structurally not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed modification-specific bifunctionality and metabolic input: IGF2BP3 reads internal m7G to degrade transcripts including TP53, while glycolysis-driven lactylation retunes its target capture in metabolic reprogramming.\",\n      \"evidence\": \"In vitro binding, dCas13b-guided site-specific m7G targeting, half-life assays, and lactylation modification/RIP assays\",\n      \"pmids\": [\"39198433\", \"39450426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for opposing m6A vs. m7G outcomes unknown\", \"How lactylation alters domain function not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that IGF2BP3 sustains serine and other metabolic programs through m6A stabilization, providing a therapeutic vulnerability via combined silencing and dietary restriction.\",\n      \"evidence\": \"CRISPR screen, RIP, mRNA stability assays, and dietary restriction in AML mouse models\",\n      \"pmids\": [\"40328743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for metabolic over other targets not mechanistically explained\", \"Normal-tissue dependence beyond hematopoiesis not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single reader discriminates among m6A (stabilizing), m7G (destabilizing), and ribonuclease-coupled fates on different transcripts, and what structural or PTM state dictates each outcome, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking domain occupancy to opposing transcript fates\", \"Rules governing partner (XRN2, exosome, HuR, stabilizer) selection unknown\", \"Quantitative competition between stabilizing and degradative modes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 11, 18, 26]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 18, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 11, 18, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 26, 53]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 42]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LIN28B\", \"XRN2\", \"ILF3\", \"PTBP1\", \"METTL14\", \"PARK2\", \"TRIM25\", \"NONO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}