{"gene":"IGF2BP2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2019,"finding":"IGF2BP2 acts as an m6A 'reader' that recognizes and binds m6A-modified SOX2 mRNA specifically at coding sequence (CDS) regions, preventing SOX2 mRNA degradation and thereby maintaining SOX2 expression in colorectal cancer cells downstream of METTL3.","method":"MeRIP-seq, RNA pull-down, RNA immunoprecipitation, RNA stability assay","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RNA pull-down and RIP with mRNA stability assay; replicated in multiple cancer contexts by independent labs","pmids":["31230592"],"is_preprint":false},{"year":2019,"finding":"LncRNA LINRIS binds IGF2BP2 and blocks K139 ubiquitination of IGF2BP2, preventing its degradation through the autophagy-lysosome pathway (ALP), thereby stabilizing IGF2BP2 protein and sustaining MYC-mediated glycolysis in colorectal cancer cells.","method":"RNA pull-down, RIP assay, ubiquitination assay, autophagy-lysosome pathway inhibition experiments","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown/RIP plus defined ubiquitination site (K139) plus ALP pathway experiments; multiple orthogonal methods in single lab","pmids":["31791342"],"is_preprint":false},{"year":2019,"finding":"IGF2BP2 binds m6A-modified lncRNA DANCR (with the critical adenosine at position 664 identified by mutagenesis) and stabilizes DANCR RNA, promoting cancer stemness-like properties in pancreatic cancer.","method":"In vivo RNA precipitation, reciprocal RNA immunoprecipitation, mutagenesis assay of m6A site","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific m6A site plus reciprocal RIP, single lab with multiple orthogonal methods","pmids":["31804607"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 promotes AML development and leukemia stem/initiation cell self-renewal by regulating expression of MYC, GPT2, and SLC1A5 in the glutamine metabolism pathway in an m6A-dependent manner; inhibition by small-molecule CWI1-2 shows anti-leukemia effects.","method":"m6A-dependent target gene regulation assays, small-molecule inhibitor (CWI1-2) in vitro and in vivo, loss-of-function with defined phenotypic readouts","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple target genes identified with m6A-dependent mechanism, validated in vivo, small-molecule inhibitor confirms target specificity","pmids":["36306790"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 binds m6A-modified TAB3 mRNA at stop codon regions, enhancing TAB3 mRNA stability; this is downstream of METTL3-mediated m6A modification and promotes renal inflammation.","method":"MeRIP-seq, RIP assay, RNA stability assay, conditional METTL3 knockout mouse model","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — MeRIP-seq combined with RIP and in vivo genetic models; multiple orthogonal methods","pmids":["35417191"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 recognizes m6A-modified EphA2 and VEGFA mRNAs (written by METTL3) and prevents their degradation, promoting vasculogenic mimicry in colorectal cancer via PI3K/AKT/mTOR and ERK1/2 signaling.","method":"CRISPR/Cas9 knockdown, RNA-seq, RIP assay, m6A reader binding confirmation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay plus functional rescue, single lab","pmids":["35595748"],"is_preprint":false},{"year":2020,"finding":"IGF2BP2 directly recognizes and binds the m6A site on FEN1 mRNA, enhancing FEN1 mRNA stability and promoting hepatocellular carcinoma proliferation in vitro and in vivo.","method":"RIP assay, RNA stability assay, overexpression and knockdown in vitro and in vivo","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and mRNA stability assay with in vivo validation, single lab","pmids":["33224879"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 stabilizes m6A-modified Slug mRNA by binding the m6A site in the CDS region of Slug, promoting EMT and lymphatic metastasis in head and neck squamous cell carcinoma.","method":"RIP, MeRIP, luciferase reporter assay, mRNA stability assay, in vivo lymphatic metastasis model","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — MeRIP plus RIP plus mRNA stability with in vivo validation, multiple orthogonal methods","pmids":["34980207"],"is_preprint":false},{"year":2010,"finding":"IMP-2 (IGF2BP2) directly binds the mRNAs of PINCH-2 and MURF-3 (confirmed by gel shift experiments), regulating their protein expression; upregulation of PINCH-2 in IMP-2-depleted myoblasts is the key event responsible for decreased cell motility; IMP-2 is also required for microtubule stabilization.","method":"Gel shift (EMSA), gain- and loss-of-function assays, transcript binding analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding confirmed by gel shift plus functional rescue experiments, single lab, multiple orthogonal methods","pmids":["20956565"],"is_preprint":false},{"year":2022,"finding":"CircEZH2 interacts with IGF2BP2 and blocks its ubiquitination-dependent degradation, stabilizing IGF2BP2; additionally, the circEZH2/IGF2BP2 complex enhances CREB1 mRNA stability in colorectal cancer.","method":"RNA pulldown, mass spectrometry, RIP, MeRIP-seq, western blot, luciferase reporter assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown, MS, and RIP in single lab with multiple orthogonal methods","pmids":["35773744"],"is_preprint":false},{"year":2021,"finding":"SUMOylation of IGF2BP2 at lysine residues K497, K505, and K509 (primarily via SUMO1) increases IGF2BP2 protein stability by blocking its ubiquitin-proteasome degradation; this modification can be reversed by SENP1. SUMOylated IGF2BP2 enhances OIP5-AS1 lncRNA stability and promotes glioma vasculogenic mimicry.","method":"Ni2+-NTA agarose bead pull-down, Co-IP, western blot, in vitro SUMOylation assay, immunoprecipitation, immunofluorescence, RIP, luciferase reporter assays","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro SUMOylation assay plus Co-IP plus mutagenesis of specific lysine sites plus SENP1 eraser identification","pmids":["34345216"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 binds to the 3'UTR of the ATP6V1A transcript and, when acetylated (due to low SIRT1 expression), recruits the XRN2 nuclease to mediate ATP6V1A transcript degradation. When SIRT1 deacetylates IGF2BP2, binding occurs but degradation does not. Thus, SIRT1-regulated acetylation of IGF2BP2 switches its function from mRNA protection to mRNA degradation.","method":"RNA binding assays, SIRT1 deacetylation assay, XRN2 recruitment assay, mRNA stability measurement, SIRT1 knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic switch established by in vitro deacetylation assay, XRN2 recruitment, and mRNA stability with multiple orthogonal methods in single rigorous study","pmids":["36322753"],"is_preprint":false},{"year":2021,"finding":"IMP2/IGF2BP2 directly binds Pdx1 mRNA and stimulates its translation in an m6A-dependent manner; additionally, IMP2 orchestrates IGF2-AKT-GSK3β-PDX1 signaling to stabilize PDX1 protein, promoting pancreatic β-cell proliferation and insulin secretion.","method":"Pancreatic β-cell-specific Imp2 knockout mice, RIP assay, m6A-dependent translation assay, signaling pathway analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model plus RIP plus m6A-dependent translation confirmation, multiple orthogonal methods","pmids":["33705986"],"is_preprint":false},{"year":2018,"finding":"Airn lncRNA binds IGF2BP2 (identified by RNA pull-down/mass spectrometry) and controls translation of several IGF2BP2-target genes in cardiomyocytes; silencing Airn reduces binding of IGF2BP2 to other mRNAs and reduces IGF2BP2 protein translation.","method":"RNA pull-down followed by mass spectrometry, further RIP assays, siRNA silencing","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown/MS for interaction discovery plus functional follow-up, single lab","pmids":["29483092"],"is_preprint":false},{"year":2016,"finding":"IGF2BP2 regulates RAF1 expression in colorectal cancer cells by protecting RAF1 mRNA from degradation by miR-195, functioning as a post-transcriptional regulatory factor that interferes with miRNA-mediated mRNA degradation.","method":"Overexpression and shRNA-mediated silencing, molecular function analyses","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, functional assays with mRNA stability; mechanism defined but limited orthogonal methods reported","pmids":["27153315"],"is_preprint":false},{"year":2016,"finding":"IGF2BP2 is a downstream target of HMGB2 in myoblasts; IGF2BP2 binds mRNAs of Myf5 and cyclin A2, enhancing Myf5 translation and cyclin A2 mRNA stabilization, respectively. Overexpression of IGF2BP2 partially rescues Myf5 and cyclin A2 protein levels upon HMGB2 depletion.","method":"Knockdown/overexpression rescue experiments, western blot, in vivo satellite cell depletion model","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiments plus in vivo model, single lab, two orthogonal methods","pmids":["27672022"],"is_preprint":false},{"year":2019,"finding":"Maternal deletion of Igf2bp2 (IMP2) in mouse embryos causes developmental arrest at the 2-cell stage; IMP2 regulates expression of Ccar1 and Rps14 required for zygotic genome activation, and IGF2 (a known IMP2 target) addition rescues developmental competence.","method":"Maternal-specific conditional knockout mice, transcriptomics, proteomics, embryo culture rescue assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined developmental phenotype plus multi-omics target identification plus IGF2 rescue experiment","pmids":["31406667"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 promotes cell cycle progression in TNBC by recognizing m6A-modified CDK6 mRNA and enhancing its translation initiation (not mRNA stability) by recruiting EIF4A1; this is dependent on m6A modification.","method":"m6A-dependent translation assay, RIP, mRNA stability assay (showing no effect), EIF4A1 co-immunoprecipitation, CDK6 reporter assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — translational (not stability) mechanism distinguished by mRNA stability assay, EIF4A1 recruitment confirmed by CoIP, m6A dependency confirmed, single lab with multiple orthogonal methods","pmids":["37983610"],"is_preprint":false},{"year":2022,"finding":"FBW7 (ubiquitin ligase) works together with GSK3β kinase to recognize and degrade IGF2BP2 through ubiquitination; conversely, IGF2BP2 enhances SLC7A5 mRNA stability and translation through m6A modification, with SLC7A5-mediated methionine transport feeding back to increase H3K4me3 at the IGF2BP2 promoter, forming a positive feedback loop promoting lung cancer radioresistance.","method":"Ubiquitination assays, Co-IP, ChIP-qPCR, RIP, MeRIP-qPCR, RNA pull-down","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ubiquitination, Co-IP, ChIP, RIP, MeRIP), feedback loop mechanistically established, single lab","pmids":["38281999"],"is_preprint":false},{"year":2023,"finding":"IGF2BP2 promotes liver cancer progression by recognizing and binding m6A-modified FLT4 mRNA (secreted via exosomes to endothelial cells), improving FLT4 RNA stability and activating the PI3K-Akt signaling pathway to promote angiogenesis.","method":"Single-cell RNA sequencing, exosome isolation, m6A modification assay, PI3K-Akt pathway analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single-cell transcriptomics plus functional m6A stability assay, but mechanism primarily from bioinformatics with limited direct biochemical binding validation in abstract","pmids":["37353784"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 recognizes m6A modification sites in IGF1R mRNA, increases IGF1R expression, and activates the RhoA-ROCK pathway to promote gastric cancer progression; this was confirmed by RIP and RNA pull-down assays.","method":"RIP assay, RNA pull-down, qRT-PCR, western blot, in vitro and in vivo functional assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP and pulldown confirmed binding, pathway activation confirmed by rescue experiments, single lab","pmids":["35306138"],"is_preprint":false},{"year":2023,"finding":"IGF2BP2 promotes glycolysis and hepatic stellate cell activation by stabilizing ALDOA (Aldolase A) mRNA via m6A-binding, generating lactate that drives histone lactylation to sustain the activated phenotype of hepatic stellate cells.","method":"m6A binding assay, mRNA stability assay, glycolysis measurement, histone lactylation analysis, loss-of-function experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-binding with mRNA stability plus histone lactylation pathway, single lab, two orthogonal mechanistic levels","pmids":["38443347"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 binds to circRUNX1 and prevents its degradation; IGF2BP2-stabilized circRUNX1 sponges miR-449b-5p to upregulate FOXP3, facilitating esophageal squamous cell carcinoma growth and metastasis.","method":"RIP assay, RNA immunoprecipitation, RNA sequencing, dual-luciferase reporter assays, rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP confirmed binding, functional rescue experiments, single lab","pmids":["36522683"],"is_preprint":false},{"year":2022,"finding":"CircRHBDD1 binds to IGF2BP2 and disrupts the interaction between E3 ligase TRIM25 and IGF2BP2, inhibiting IGF2BP2 ubiquitination and degradation; stabilized IGF2BP2 then enhances PD-L1 mRNA stability through m6A modification to promote immune escape in gastric cancer.","method":"RNA immunoprecipitation, Co-IP, meRIP analysis, ubiquitination assay, flow cytometry","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for TRIM25-IGF2BP2 interaction, ubiquitination assay, meRIP for m6A; single lab, multiple orthogonal methods","pmids":["39080693"],"is_preprint":false},{"year":2024,"finding":"METTL14-mediated m6A modification stabilizes GluN2A subunit (NMDAR) expression via IGF2BP2 in DRG neurons; METTL14-mediated m6A facilitates synaptic plasticity and pain hypersensitivity through this IGF2BP2-dependent mechanism.","method":"Dot blotting, immunofluorescence, gain/loss-of-function, behavioral assays, RIP (implied from m6A-IGF2BP2-dependent mechanism)","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro genetic models with defined pathway (METTL14→m6A→IGF2BP2→GluN2A), single lab","pmids":["38319733"],"is_preprint":false},{"year":2024,"finding":"METTL14-mediated m6A modification of NLRP3 mRNA is recognized by IGF2BP2, which stabilizes NLRP3 mRNA; IGF2BP2 knockdown diminishes LPS-induced acute lung injury in mice by downregulating NLRP3 expression.","method":"MeRIP, RIP assay, in vitro macrophage experiments, mouse ALI model with IGF2BP2 knockdown","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — MeRIP plus RIP with in vivo genetic validation (knockdown), multiple orthogonal methods confirming mechanism","pmids":["38218935"],"is_preprint":false},{"year":2022,"finding":"Igf2bp2 deletion in young mice reduces oxidative metabolism and impairs colony formation and HSC repopulation capacity, mimicking aging-related changes; Igf2bp2-deficient aged mice show amelioration of aging-associated HSC expansion and myeloid skewing, indicating Igf2bp2 regulates mitochondrial metabolism and stemness of young HSCs.","method":"Igf2bp2 knockout mouse model, RNA sequencing, colony formation assays, bone marrow transplantation/repopulation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-characterized KO mouse model with multiple functional readouts (repopulation, colony, transcriptomics), in vivo validation","pmids":["35231105"],"is_preprint":false},{"year":2023,"finding":"LCAT1 lncRNA physically interacts with and stabilizes IGF2BP2 by preventing its degradation via autolysosomes; the LCAT1/IGF2BP2 complex then increases CDC6 mRNA levels by stabilizing CDC6 mRNA in an m6A-dependent manner, promoting lung cancer progression.","method":"RNA pulldown, Co-IP, RIP, m6A-dependent mRNA stability assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown/RIP plus mRNA stability in single lab; autolysosome degradation mechanism defined","pmids":["36257938"],"is_preprint":false},{"year":2023,"finding":"IGF2BP2 overexpression in cardiomyocytes leads to dilated cardiomyopathy (DCM) with downregulation of sarcomeric and mitochondrial proteins and fragmented mitochondria; downregulating the IGF2BP2 transgene after 2 weeks rescues DCM, demonstrating reversible pathological role.","method":"Conditional inducible transgenic mouse model, cardiac phenotyping, proteomics","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible transgenic mouse model with reversible phenotype, in vivo functional readouts (cardiac function, proteomics)","pmids":["38052926"],"is_preprint":false},{"year":2023,"finding":"IMP2/IGF2BP2 binds Wnt receptor Fzd8 mRNA and promotes its degradation by recruiting the CCR4-NOT deadenylase complex in an mTOR-dependent manner in mesenchymal stem cells, controlling adipogenic commitment and white adipose tissue homeostasis.","method":"Conditional MSC-specific Imp2 knockout mice, RIP assay, mRNA stability analysis, mTOR pathway inhibition","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model plus RIP plus CCR4-NOT recruitment plus mTOR dependency, multiple orthogonal methods, single lab","pmids":["36219823"],"is_preprint":false},{"year":2024,"finding":"First small-molecule inhibitors of IGF2BP2/IMP2 were identified and validated: compounds from benzamidobenzoic acid and ureidothiophene classes were confirmed to bind IMP2 by fluorescence polarization assay, thermal shift assay, and saturation-transfer difference NMR, and showed biological activity reducing tumor cell proliferation in vitro and in xenograft models.","method":"Fluorescence polarization assay, thermal shift assay, saturation-transfer difference NMR, 2D/3D cell culture, zebrafish xenotransplant in vivo","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — three orthogonal biophysical binding methods plus in vitro and in vivo functional validation, single lab","pmids":["35023719"],"is_preprint":false},{"year":2022,"finding":"Circ-TNPO3 directly binds IGF2BP2 protein (via RNA pull-down and RIP), and this interaction destabilizes SERPINH1 mRNA, suppressing ccRCC metastasis; rescue experiments confirmed that IGF2BP2/SERPINH1 axis mediates the tumor-suppressive function of circ-TNPO3.","method":"RNA pull-down, RNA immunoprecipitation, RIP, FISH, rescue assays, in vitro and in vivo models","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown/RIP plus rescue experiments in single lab; mechanistic direction (destabilization) is notable but single lab","pmids":["35876041"],"is_preprint":false},{"year":2024,"finding":"IGF2BP2 regulates the stability of GSTM5 mRNA in fibroblast-like synoviocytes, and the IGF2BP2-GSTM5 axis controls inflammatory responses and MMP9/MMP13 expression in rheumatoid arthritis; intra-articular AAV-mediated IGF2BP2 overexpression relieved arthritis in a CIA rat model.","method":"RNA sequencing, RIP (implied), in vivo CIA rat model with AAV overexpression, mRNA stability assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with AAV plus mRNA stability and functional readouts; target (GSTM5) identified by sequencing, single lab","pmids":["38702323"],"is_preprint":false},{"year":2021,"finding":"Let-7e-5p directly downregulates Igf2bp2 expression at the mRNA and protein level in C2C12 myotube cells, inhibiting myosin heavy chain expression and impairing mitochondrial function and glucose uptake, causing muscle atrophy.","method":"microRNA overexpression/knockdown, RT-PCR, western blot in C2C12 myotubes","journal":"Frontiers in endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single indirect measurement of IGF2BP2 as miRNA target without direct binding assay","pmids":["35002969"],"is_preprint":false},{"year":2024,"finding":"circHIPK3 contains an 11-mer motif that constitutes a strong IGF2BP2 binding site; circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates, sequestering IGF2BP2 as a competing endogenous RNA and regulating STAT3 mRNA stability via IGF2BP2.","method":"eCLIP dataset mining, RIP assay, absolute copy number quantification, RNA sequencing, phase separation analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — eCLIP plus RIP, motif mutagenesis implied, copy number quantification, phase separation evidence, multiple orthogonal approaches","pmids":["39041323"],"is_preprint":false},{"year":2024,"finding":"High matrix stiffness in pancreatic cancer stabilizes IGF2BP2, which promotes sphingomyelin synthesis via SGMS2 upregulation; this pathway facilitates PD-L1 localization on membrane lipid rafts, enhancing immune evasion.","method":"MeRIP, RIP, RNA pull-down, single-cell RNA-sequencing, flow cytometry, multiplex IHC, humanized mouse models, PDAC organoids","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MeRIP, RIP, pulldown, in vivo humanized mouse model, multiple orthogonal methods; mechanistic axis (stiffness→IGF2BP2→SGMS2→lipid rafts→PD-L1) defined","pmids":["40158738"],"is_preprint":false},{"year":2024,"finding":"TRIM15 ubiquitinates IGF2BP2, which enhances IGF2BP2's function in phase separation and maintenance of TLR4 mRNA stability in pancreatic cancer; IGF2BP2 combines with TLR4 to inhibit its mRNA degradation.","method":"Transcriptomics, proteomics, Co-IP, ubiquitination assay, in vivo orthotopic mouse model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay plus in vivo model; TRIM15-IGF2BP2-TLR4 axis defined, single lab","pmids":["38657551"],"is_preprint":false},{"year":2024,"finding":"IGF2BP2 directly interacts with CD5L and CD36 mRNA (confirmed by RIP), stabilizing their expression; in osteoclastogenesis during periodontitis, IGF2BP2 regulates osteoclast differentiation via CD36 and CD5L, and its deficiency exacerbates early-stage inflammation but reduces osteoclast differentiation at later stages.","method":"RIP assay, AAV-mediated knockdown, ligature-induced periodontitis mouse model, overexpression rescue experiments","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirmed direct mRNA binding plus in vivo mouse model, rescue experiments, single lab","pmids":["38193302"],"is_preprint":false},{"year":2025,"finding":"A circular RNA (circRNA-BISC) contains a 'CAC-linker-XGGX' motif that specifically binds IGF2BP2 (but not IGF2BP1 or IGF2BP3), inhibiting IGF2BP2-mediated translation enhancement of c-MYC mRNA and overcoming BETi resistance in TNBC.","method":"RIP-Seq, RNA immunoprecipitation, in vitro transcribed circRNA functional assays, cell and in vivo BETi-resistant TNBC models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP-Seq plus functional in vitro and in vivo validation, selectivity for IGF2BP2 over paralogs demonstrated, motif identified","pmids":["40591591"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 promotes YAP mRNA translation by recognizing its m6A modification in colorectal cancer; YAP subsequently promotes TEAD4 enrichment at the ErbB2 promoter to upregulate ErbB2 expression.","method":"RIP assay, m6A recognition, promoter enrichment assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP for m6A recognition plus functional rescue, single lab","pmids":["34309973"],"is_preprint":false},{"year":2024,"finding":"IGF2BP2 stabilizes m6A-modified FOSL1 mRNA in trophoblast cells in an IGF2BP2-dependent manner downstream of METTL3; elevated FOSL1 inhibits trophoblast invasion, contributing to fetal growth restriction.","method":"MeRIP-seq, RNA-seq, RIP assay, mRNA stability assay, in vivo FGR mouse model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP plus in vivo model; single lab, multiple orthogonal methods","pmids":["39565355"],"is_preprint":false}],"current_model":"IGF2BP2 (IMP-2) is an m6A 'reader' RNA-binding protein that primarily recognizes N6-methyladenosine-modified mRNAs (and certain non-coding RNAs) at CDS or 3'UTR regions to stabilize them against degradation, and in some contexts (e.g., CDK6, EIF4A1, c-MYC) enhances their translation initiation by recruiting factors such as EIF4A1; its activity is regulated post-translationally by SIRT1-mediated acetylation (switching it between mRNA protection and degradation of specific targets like ATP6V1A), by SUMO1-mediated SUMOylation at K497/K505/K509 (blocking proteasomal degradation), by K139 ubiquitination (targeting it to autolysosomes), and by interactions with various lncRNAs and circRNAs that competitively block its ubiquitination or nucleate it into phase-separated condensates; its diverse m6A-dependent targets include SOX2, MYC, FEN1, Slug, PDX1, Fzd8, Pdx1, CDK6, NLRP3, TAB3, and many others, placing it at the intersection of post-transcriptional gene regulation, metabolism, immune function, and cancer progression."},"narrative":{"mechanistic_narrative":"IGF2BP2 (IMP-2) is a sequence- and modification-specific RNA-binding protein that operates as a post-transcriptional regulatory hub, predominantly acting as an N6-methyladenosine (m6A) 'reader' that binds methylated transcripts at CDS, stop-codon, or 3'UTR regions to control their stability and translation [PMID:31230592, PMID:35417191, PMID:34980207]. Its canonical output is target-mRNA protection: by recognizing m6A marks written by METTL3/METTL14, IGF2BP2 shields transcripts such as SOX2, FEN1, Slug, TAB3, and NLRP3 from degradation, thereby sustaining programs in cancer proliferation, EMT/metastasis, and inflammation [PMID:31230592, PMID:33224879, PMID:34980207, PMID:35417191, PMID:38218935]. Beyond stabilization, IGF2BP2 can enhance translation initiation of m6A-modified targets — for CDK6 it does so without altering mRNA levels by recruiting EIF4A1, and it similarly drives translation of Pdx1, YAP, and c-MYC [PMID:37983610, PMID:33705986, PMID:34309973, PMID:40591591]. IGF2BP2 also operates as a negative regulator in defined contexts, recruiting the XRN2 nuclease or the CCR4-NOT deadenylase to destabilize specific transcripts (ATP6V1A, Fzd8) depending on its modification state and signaling input [PMID:36322753, PMID:36219823]. This functional switching is set by post-translational control: SIRT1-regulated acetylation toggles IGF2BP2 between mRNA protection and degradation [PMID:36322753], SUMO1-mediated SUMOylation at K497/K505/K509 blocks proteasomal turnover [PMID:34345216], and competing E3 ligases (FBW7/GSK3β, TRIM25, TRIM15) drive its ubiquitination and degradation [PMID:38281999, PMID:39080693, PMID:38657551]. A large family of lncRNAs and circRNAs (LINRIS, circEZH2, circRHBDD1, LCAT1, circHIPK3, circRNA-BISC) bind IGF2BP2 to block its ubiquitination, nucleate it into phase-separated condensates, or competitively inhibit its translational activity [PMID:31791342, PMID:35773744, PMID:39080693, PMID:39041323, PMID:40591591]. Genetically, IGF2BP2 is required for diverse developmental and metabolic programs, including zygotic genome activation at the 2-cell stage, pancreatic β-cell proliferation and insulin secretion, hematopoietic stem cell mitochondrial metabolism and self-renewal, and cardiomyocyte homeostasis, where its forced overexpression produces reversible dilated cardiomyopathy [PMID:31406667, PMID:33705986, PMID:35231105, PMID:38052926]. Earlier work established its role in muscle, where it binds PINCH-2, MURF-3, Myf5, and cyclin A2 transcripts and supports microtubule stabilization and myoblast function [PMID:20956565, PMID:27672022].","teleology":[{"year":2010,"claim":"Established IGF2BP2 as a direct mRNA-binding regulator of protein output before its m6A-reader role was known, anchoring its function in cytoskeletal and motility control.","evidence":"Gel-shift (EMSA) and gain/loss-of-function in myoblasts identifying PINCH-2 and MURF-3 as bound transcripts and a requirement for microtubule stabilization","pmids":["20956565"],"confidence":"High","gaps":["No m6A dependency tested at this stage","Mechanism of stabilization vs translation control not distinguished"]},{"year":2016,"claim":"Showed IGF2BP2 protects target mRNAs from miRNA-mediated decay and acts downstream of upstream regulators, broadening its role to competitive post-transcriptional control.","evidence":"shRNA/overexpression studies of RAF1 vs miR-195 in colorectal cancer, and rescue experiments placing IGF2BP2 downstream of HMGB2 for Myf5/cyclin A2 in myoblasts","pmids":["27153315","27672022"],"confidence":"Medium","gaps":["Direct binding not always confirmed by orthogonal biophysical assays","m6A involvement not addressed"]},{"year":2019,"claim":"Defined IGF2BP2 as a bona fide m6A reader that stabilizes methylated transcripts and ncRNAs, establishing its central modern mechanism.","evidence":"MeRIP-seq, reciprocal RNA pull-down/RIP, and m6A-site mutagenesis for SOX2 mRNA (CDS) and DANCR lncRNA downstream of METTL3 in colorectal and pancreatic cancer","pmids":["31230592","31804607"],"confidence":"High","gaps":["Whether reading is stabilization or translation was not generalized","Reader specificity over IGF2BP1/3 not addressed"]},{"year":2019,"claim":"Identified the first layer of IGF2BP2 protein-stability control by lncRNA, linking its abundance to glycolytic and developmental programs.","evidence":"RNA pull-down/RIP and ubiquitination assays showing LINRIS blocks K139 ubiquitination and autophagy-lysosome degradation; maternal conditional KO showing 2-cell arrest and IGF2 rescue","pmids":["31791342","31406667"],"confidence":"High","gaps":["Identity of the K139 E3 ligase not established here","Direct targets driving ZGA arrest only partially defined"]},{"year":2021,"claim":"Resolved post-translational regulation of IGF2BP2 by SUMOylation and demonstrated m6A-dependent translational (not just stability) control of a physiological target.","evidence":"In vitro SUMOylation, Co-IP, and lysine mutagenesis (K497/K505/K509, SENP1 eraser); β-cell-specific Imp2 KO with RIP and m6A-dependent Pdx1 translation assays","pmids":["34345216","33705986"],"confidence":"High","gaps":["Interplay between SUMOylation and ubiquitination not quantified","Generality of translational enhancement across targets unresolved"]},{"year":2022,"claim":"Established IGF2BP2 as a switchable regulator that can also degrade transcripts and recruit distinct effectors, and confirmed it as a druggable cancer target.","evidence":"SIRT1-acetylation/XRN2 recruitment switch on ATP6V1A; CCR4-NOT/mTOR-dependent Fzd8 degradation in MSCs; EIF4A1 recruitment for CDK6 translation; small-molecule CWI1-2 and biophysically validated inhibitors","pmids":["36322753","36219823","37983610","36306790","35023719"],"confidence":"High","gaps":["Determinants choosing protection vs degradation per transcript incompletely mapped","Direct vs indirect effector recruitment not structurally resolved"]},{"year":2022,"claim":"Expanded the regulatory network controlling IGF2BP2 abundance through multiple E3 ligases and circRNA/lncRNA shields, and demonstrated feedback loops.","evidence":"Co-IP/ubiquitination assays for FBW7-GSK3β and TRIM25 (blocked by circRHBDD1); circEZH2 and circRUNX1 stabilization of IGF2BP2; SLC7A5-H3K4me3 positive feedback at the IGF2BP2 promoter","pmids":["38281999","39080693","35773744","36522683"],"confidence":"High","gaps":["Relative contribution of competing E3 ligases in vivo unknown","Stoichiometry of circRNA shielding not defined"]},{"year":2023,"claim":"Demonstrated genetic requirements of IGF2BP2 in stem-cell metabolism and cardiac homeostasis, showing dose- and reversibility-dependent pathology.","evidence":"Igf2bp2 KO mice showing impaired HSC oxidative metabolism and repopulation; inducible cardiomyocyte transgenic mice with reversible dilated cardiomyopathy","pmids":["35231105","38052926"],"confidence":"High","gaps":["Direct mitochondrial/sarcomeric mRNA targets not fully enumerated","Mechanism linking IGF2BP2 to mitochondrial fragmentation unresolved"]},{"year":2024,"claim":"Defined IGF2BP2 as a driver of immune evasion and inflammation across tissues, and established sequence-specific, paralog-selective circRNA antagonism via phase separation.","evidence":"MeRIP/RIP and in vivo models linking IGF2BP2 to NLRP3, PD-L1 (via SGMS2/lipid rafts and matrix stiffness), TLR4; circHIPK3 and circRNA-BISC motif-specific binding and condensate formation","pmids":["38218935","40158738","38657551","39041323","40591591"],"confidence":"High","gaps":["Structural basis of condensate assembly not solved","Whether phase separation alters target selectivity globally unknown"]},{"year":null,"claim":"How IGF2BP2 integrates competing post-translational modifications, condensate formation, and m6A reading to deterministically select between stabilizing, degrading, or translationally enhancing a given transcript remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified structural model of the reader-effector interface","Genome-wide rules predicting protection vs degradation are lacking","Physiological hierarchy among acetylation, SUMOylation, and ubiquitination not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,7,8,17,34]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[12,17,39,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,14,29]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,34]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,7,11,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,6,7,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,23,25,35]}],"complexes":[],"partners":["EIF4A1","XRN2","CCR4-NOT","SIRT1","FBW7","TRIM25","TRIM15","SENP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6M1","full_name":"Insulin-like growth factor 2 mRNA-binding protein 2","aliases":["Hepatocellular carcinoma autoantigen p62","IGF-II mRNA-binding protein 2","VICKZ family member 2"],"length_aa":599,"mass_kda":66.1,"function":"RNA-binding factor that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs). 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Increases MYC mRNA stability by binding to the coding region instability determinant (CRD) and binding is enhanced by m6A-modification of the CRD (PubMed:29476152)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, P-body; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9Y6M1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF2BP2","classification":"Not 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IGF2BP1","url":"https://www.omim.org/entry/608288"},{"mim_id":"600698","title":"HIGH MOBILITY GROUP AT-HOOK 2; HMGA2","url":"https://www.omim.org/entry/600698"},{"mim_id":"147470","title":"INSULIN-LIKE GROWTH FACTOR II; IGF2","url":"https://www.omim.org/entry/147470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IGF2BP2"},"hgnc":{"alias_symbol":["IMP-2","p62","P62"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6M1","domains":[{"cath_id":"3.30.70.330","chopping":"4-74","consensus_level":"high","plddt":84.9849,"start":4,"end":74},{"cath_id":"3.30.70.330","chopping":"84-155","consensus_level":"high","plddt":83.1088,"start":84,"end":155},{"cath_id":"3.30.310.210","chopping":"197-356","consensus_level":"medium","plddt":88.7897,"start":197,"end":356},{"cath_id":"3.30.310.210","chopping":"429-587","consensus_level":"medium","plddt":89.4014,"start":429,"end":587}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6M1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6M1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6M1-F1-predicted_aligned_error_v6.png","plddt_mean":77.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGF2BP2","jax_strain_url":"https://www.jax.org/strain/search?query=IGF2BP2"},"sequence":{"accession":"Q9Y6M1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6M1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6M1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6M1"}},"corpus_meta":[{"pmid":"31230592","id":"PMC_31230592","title":"METTL3 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replicated in multiple cancer contexts by independent labs\",\n      \"pmids\": [\"31230592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LncRNA LINRIS binds IGF2BP2 and blocks K139 ubiquitination of IGF2BP2, preventing its degradation through the autophagy-lysosome pathway (ALP), thereby stabilizing IGF2BP2 protein and sustaining MYC-mediated glycolysis in colorectal cancer cells.\",\n      \"method\": \"RNA pull-down, RIP assay, ubiquitination assay, autophagy-lysosome pathway inhibition experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown/RIP plus defined ubiquitination site (K139) plus ALP pathway experiments; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"31791342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGF2BP2 binds m6A-modified lncRNA DANCR (with the critical adenosine at position 664 identified by mutagenesis) and stabilizes DANCR RNA, promoting cancer stemness-like properties in pancreatic cancer.\",\n      \"method\": \"In vivo RNA precipitation, reciprocal RNA immunoprecipitation, mutagenesis assay of m6A site\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific m6A site plus reciprocal RIP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31804607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 promotes AML development and leukemia stem/initiation cell self-renewal by regulating expression of MYC, GPT2, and SLC1A5 in the glutamine metabolism pathway in an m6A-dependent manner; inhibition by small-molecule CWI1-2 shows anti-leukemia effects.\",\n      \"method\": \"m6A-dependent target gene regulation assays, small-molecule inhibitor (CWI1-2) in vitro and in vivo, loss-of-function with defined phenotypic readouts\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple target genes identified with m6A-dependent mechanism, validated in vivo, small-molecule inhibitor confirms target specificity\",\n      \"pmids\": [\"36306790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 binds m6A-modified TAB3 mRNA at stop codon regions, enhancing TAB3 mRNA stability; this is downstream of METTL3-mediated m6A modification and promotes renal inflammation.\",\n      \"method\": \"MeRIP-seq, RIP assay, RNA stability assay, conditional METTL3 knockout mouse model\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MeRIP-seq combined with RIP and in vivo genetic models; multiple orthogonal methods\",\n      \"pmids\": [\"35417191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 recognizes m6A-modified EphA2 and VEGFA mRNAs (written by METTL3) and prevents their degradation, promoting vasculogenic mimicry in colorectal cancer via PI3K/AKT/mTOR and ERK1/2 signaling.\",\n      \"method\": \"CRISPR/Cas9 knockdown, RNA-seq, RIP assay, m6A reader binding confirmation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay plus functional rescue, single lab\",\n      \"pmids\": [\"35595748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF2BP2 directly recognizes and binds the m6A site on FEN1 mRNA, enhancing FEN1 mRNA stability and promoting hepatocellular carcinoma proliferation in vitro and in vivo.\",\n      \"method\": \"RIP assay, RNA stability assay, overexpression and knockdown in vitro and in vivo\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and mRNA stability assay with in vivo validation, single lab\",\n      \"pmids\": [\"33224879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 stabilizes m6A-modified Slug mRNA by binding the m6A site in the CDS region of Slug, promoting EMT and lymphatic metastasis in head and neck squamous cell carcinoma.\",\n      \"method\": \"RIP, MeRIP, luciferase reporter assay, mRNA stability assay, in vivo lymphatic metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MeRIP plus RIP plus mRNA stability with in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"34980207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IMP-2 (IGF2BP2) directly binds the mRNAs of PINCH-2 and MURF-3 (confirmed by gel shift experiments), regulating their protein expression; upregulation of PINCH-2 in IMP-2-depleted myoblasts is the key event responsible for decreased cell motility; IMP-2 is also required for microtubule stabilization.\",\n      \"method\": \"Gel shift (EMSA), gain- and loss-of-function assays, transcript binding analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding confirmed by gel shift plus functional rescue experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20956565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircEZH2 interacts with IGF2BP2 and blocks its ubiquitination-dependent degradation, stabilizing IGF2BP2; additionally, the circEZH2/IGF2BP2 complex enhances CREB1 mRNA stability in colorectal cancer.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RIP, MeRIP-seq, western blot, luciferase reporter assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown, MS, and RIP in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35773744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUMOylation of IGF2BP2 at lysine residues K497, K505, and K509 (primarily via SUMO1) increases IGF2BP2 protein stability by blocking its ubiquitin-proteasome degradation; this modification can be reversed by SENP1. SUMOylated IGF2BP2 enhances OIP5-AS1 lncRNA stability and promotes glioma vasculogenic mimicry.\",\n      \"method\": \"Ni2+-NTA agarose bead pull-down, Co-IP, western blot, in vitro SUMOylation assay, immunoprecipitation, immunofluorescence, RIP, luciferase reporter assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro SUMOylation assay plus Co-IP plus mutagenesis of specific lysine sites plus SENP1 eraser identification\",\n      \"pmids\": [\"34345216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 binds to the 3'UTR of the ATP6V1A transcript and, when acetylated (due to low SIRT1 expression), recruits the XRN2 nuclease to mediate ATP6V1A transcript degradation. When SIRT1 deacetylates IGF2BP2, binding occurs but degradation does not. Thus, SIRT1-regulated acetylation of IGF2BP2 switches its function from mRNA protection to mRNA degradation.\",\n      \"method\": \"RNA binding assays, SIRT1 deacetylation assay, XRN2 recruitment assay, mRNA stability measurement, SIRT1 knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic switch established by in vitro deacetylation assay, XRN2 recruitment, and mRNA stability with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36322753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IMP2/IGF2BP2 directly binds Pdx1 mRNA and stimulates its translation in an m6A-dependent manner; additionally, IMP2 orchestrates IGF2-AKT-GSK3β-PDX1 signaling to stabilize PDX1 protein, promoting pancreatic β-cell proliferation and insulin secretion.\",\n      \"method\": \"Pancreatic β-cell-specific Imp2 knockout mice, RIP assay, m6A-dependent translation assay, signaling pathway analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model plus RIP plus m6A-dependent translation confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"33705986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Airn lncRNA binds IGF2BP2 (identified by RNA pull-down/mass spectrometry) and controls translation of several IGF2BP2-target genes in cardiomyocytes; silencing Airn reduces binding of IGF2BP2 to other mRNAs and reduces IGF2BP2 protein translation.\",\n      \"method\": \"RNA pull-down followed by mass spectrometry, further RIP assays, siRNA silencing\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown/MS for interaction discovery plus functional follow-up, single lab\",\n      \"pmids\": [\"29483092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF2BP2 regulates RAF1 expression in colorectal cancer cells by protecting RAF1 mRNA from degradation by miR-195, functioning as a post-transcriptional regulatory factor that interferes with miRNA-mediated mRNA degradation.\",\n      \"method\": \"Overexpression and shRNA-mediated silencing, molecular function analyses\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, functional assays with mRNA stability; mechanism defined but limited orthogonal methods reported\",\n      \"pmids\": [\"27153315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGF2BP2 is a downstream target of HMGB2 in myoblasts; IGF2BP2 binds mRNAs of Myf5 and cyclin A2, enhancing Myf5 translation and cyclin A2 mRNA stabilization, respectively. Overexpression of IGF2BP2 partially rescues Myf5 and cyclin A2 protein levels upon HMGB2 depletion.\",\n      \"method\": \"Knockdown/overexpression rescue experiments, western blot, in vivo satellite cell depletion model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiments plus in vivo model, single lab, two orthogonal methods\",\n      \"pmids\": [\"27672022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Maternal deletion of Igf2bp2 (IMP2) in mouse embryos causes developmental arrest at the 2-cell stage; IMP2 regulates expression of Ccar1 and Rps14 required for zygotic genome activation, and IGF2 (a known IMP2 target) addition rescues developmental competence.\",\n      \"method\": \"Maternal-specific conditional knockout mice, transcriptomics, proteomics, embryo culture rescue assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined developmental phenotype plus multi-omics target identification plus IGF2 rescue experiment\",\n      \"pmids\": [\"31406667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 promotes cell cycle progression in TNBC by recognizing m6A-modified CDK6 mRNA and enhancing its translation initiation (not mRNA stability) by recruiting EIF4A1; this is dependent on m6A modification.\",\n      \"method\": \"m6A-dependent translation assay, RIP, mRNA stability assay (showing no effect), EIF4A1 co-immunoprecipitation, CDK6 reporter assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — translational (not stability) mechanism distinguished by mRNA stability assay, EIF4A1 recruitment confirmed by CoIP, m6A dependency confirmed, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37983610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBW7 (ubiquitin ligase) works together with GSK3β kinase to recognize and degrade IGF2BP2 through ubiquitination; conversely, IGF2BP2 enhances SLC7A5 mRNA stability and translation through m6A modification, with SLC7A5-mediated methionine transport feeding back to increase H3K4me3 at the IGF2BP2 promoter, forming a positive feedback loop promoting lung cancer radioresistance.\",\n      \"method\": \"Ubiquitination assays, Co-IP, ChIP-qPCR, RIP, MeRIP-qPCR, RNA pull-down\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ubiquitination, Co-IP, ChIP, RIP, MeRIP), feedback loop mechanistically established, single lab\",\n      \"pmids\": [\"38281999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP2 promotes liver cancer progression by recognizing and binding m6A-modified FLT4 mRNA (secreted via exosomes to endothelial cells), improving FLT4 RNA stability and activating the PI3K-Akt signaling pathway to promote angiogenesis.\",\n      \"method\": \"Single-cell RNA sequencing, exosome isolation, m6A modification assay, PI3K-Akt pathway analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single-cell transcriptomics plus functional m6A stability assay, but mechanism primarily from bioinformatics with limited direct biochemical binding validation in abstract\",\n      \"pmids\": [\"37353784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 recognizes m6A modification sites in IGF1R mRNA, increases IGF1R expression, and activates the RhoA-ROCK pathway to promote gastric cancer progression; this was confirmed by RIP and RNA pull-down assays.\",\n      \"method\": \"RIP assay, RNA pull-down, qRT-PCR, western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP and pulldown confirmed binding, pathway activation confirmed by rescue experiments, single lab\",\n      \"pmids\": [\"35306138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP2 promotes glycolysis and hepatic stellate cell activation by stabilizing ALDOA (Aldolase A) mRNA via m6A-binding, generating lactate that drives histone lactylation to sustain the activated phenotype of hepatic stellate cells.\",\n      \"method\": \"m6A binding assay, mRNA stability assay, glycolysis measurement, histone lactylation analysis, loss-of-function experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-binding with mRNA stability plus histone lactylation pathway, single lab, two orthogonal mechanistic levels\",\n      \"pmids\": [\"38443347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 binds to circRUNX1 and prevents its degradation; IGF2BP2-stabilized circRUNX1 sponges miR-449b-5p to upregulate FOXP3, facilitating esophageal squamous cell carcinoma growth and metastasis.\",\n      \"method\": \"RIP assay, RNA immunoprecipitation, RNA sequencing, dual-luciferase reporter assays, rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP confirmed binding, functional rescue experiments, single lab\",\n      \"pmids\": [\"36522683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircRHBDD1 binds to IGF2BP2 and disrupts the interaction between E3 ligase TRIM25 and IGF2BP2, inhibiting IGF2BP2 ubiquitination and degradation; stabilized IGF2BP2 then enhances PD-L1 mRNA stability through m6A modification to promote immune escape in gastric cancer.\",\n      \"method\": \"RNA immunoprecipitation, Co-IP, meRIP analysis, ubiquitination assay, flow cytometry\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for TRIM25-IGF2BP2 interaction, ubiquitination assay, meRIP for m6A; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39080693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14-mediated m6A modification stabilizes GluN2A subunit (NMDAR) expression via IGF2BP2 in DRG neurons; METTL14-mediated m6A facilitates synaptic plasticity and pain hypersensitivity through this IGF2BP2-dependent mechanism.\",\n      \"method\": \"Dot blotting, immunofluorescence, gain/loss-of-function, behavioral assays, RIP (implied from m6A-IGF2BP2-dependent mechanism)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro genetic models with defined pathway (METTL14→m6A→IGF2BP2→GluN2A), single lab\",\n      \"pmids\": [\"38319733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14-mediated m6A modification of NLRP3 mRNA is recognized by IGF2BP2, which stabilizes NLRP3 mRNA; IGF2BP2 knockdown diminishes LPS-induced acute lung injury in mice by downregulating NLRP3 expression.\",\n      \"method\": \"MeRIP, RIP assay, in vitro macrophage experiments, mouse ALI model with IGF2BP2 knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MeRIP plus RIP with in vivo genetic validation (knockdown), multiple orthogonal methods confirming mechanism\",\n      \"pmids\": [\"38218935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Igf2bp2 deletion in young mice reduces oxidative metabolism and impairs colony formation and HSC repopulation capacity, mimicking aging-related changes; Igf2bp2-deficient aged mice show amelioration of aging-associated HSC expansion and myeloid skewing, indicating Igf2bp2 regulates mitochondrial metabolism and stemness of young HSCs.\",\n      \"method\": \"Igf2bp2 knockout mouse model, RNA sequencing, colony formation assays, bone marrow transplantation/repopulation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-characterized KO mouse model with multiple functional readouts (repopulation, colony, transcriptomics), in vivo validation\",\n      \"pmids\": [\"35231105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LCAT1 lncRNA physically interacts with and stabilizes IGF2BP2 by preventing its degradation via autolysosomes; the LCAT1/IGF2BP2 complex then increases CDC6 mRNA levels by stabilizing CDC6 mRNA in an m6A-dependent manner, promoting lung cancer progression.\",\n      \"method\": \"RNA pulldown, Co-IP, RIP, m6A-dependent mRNA stability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown/RIP plus mRNA stability in single lab; autolysosome degradation mechanism defined\",\n      \"pmids\": [\"36257938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGF2BP2 overexpression in cardiomyocytes leads to dilated cardiomyopathy (DCM) with downregulation of sarcomeric and mitochondrial proteins and fragmented mitochondria; downregulating the IGF2BP2 transgene after 2 weeks rescues DCM, demonstrating reversible pathological role.\",\n      \"method\": \"Conditional inducible transgenic mouse model, cardiac phenotyping, proteomics\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible transgenic mouse model with reversible phenotype, in vivo functional readouts (cardiac function, proteomics)\",\n      \"pmids\": [\"38052926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IMP2/IGF2BP2 binds Wnt receptor Fzd8 mRNA and promotes its degradation by recruiting the CCR4-NOT deadenylase complex in an mTOR-dependent manner in mesenchymal stem cells, controlling adipogenic commitment and white adipose tissue homeostasis.\",\n      \"method\": \"Conditional MSC-specific Imp2 knockout mice, RIP assay, mRNA stability analysis, mTOR pathway inhibition\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model plus RIP plus CCR4-NOT recruitment plus mTOR dependency, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36219823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"First small-molecule inhibitors of IGF2BP2/IMP2 were identified and validated: compounds from benzamidobenzoic acid and ureidothiophene classes were confirmed to bind IMP2 by fluorescence polarization assay, thermal shift assay, and saturation-transfer difference NMR, and showed biological activity reducing tumor cell proliferation in vitro and in xenograft models.\",\n      \"method\": \"Fluorescence polarization assay, thermal shift assay, saturation-transfer difference NMR, 2D/3D cell culture, zebrafish xenotransplant in vivo\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — three orthogonal biophysical binding methods plus in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"35023719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Circ-TNPO3 directly binds IGF2BP2 protein (via RNA pull-down and RIP), and this interaction destabilizes SERPINH1 mRNA, suppressing ccRCC metastasis; rescue experiments confirmed that IGF2BP2/SERPINH1 axis mediates the tumor-suppressive function of circ-TNPO3.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, RIP, FISH, rescue assays, in vitro and in vivo models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown/RIP plus rescue experiments in single lab; mechanistic direction (destabilization) is notable but single lab\",\n      \"pmids\": [\"35876041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP2 regulates the stability of GSTM5 mRNA in fibroblast-like synoviocytes, and the IGF2BP2-GSTM5 axis controls inflammatory responses and MMP9/MMP13 expression in rheumatoid arthritis; intra-articular AAV-mediated IGF2BP2 overexpression relieved arthritis in a CIA rat model.\",\n      \"method\": \"RNA sequencing, RIP (implied), in vivo CIA rat model with AAV overexpression, mRNA stability assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with AAV plus mRNA stability and functional readouts; target (GSTM5) identified by sequencing, single lab\",\n      \"pmids\": [\"38702323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Let-7e-5p directly downregulates Igf2bp2 expression at the mRNA and protein level in C2C12 myotube cells, inhibiting myosin heavy chain expression and impairing mitochondrial function and glucose uptake, causing muscle atrophy.\",\n      \"method\": \"microRNA overexpression/knockdown, RT-PCR, western blot in C2C12 myotubes\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single indirect measurement of IGF2BP2 as miRNA target without direct binding assay\",\n      \"pmids\": [\"35002969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circHIPK3 contains an 11-mer motif that constitutes a strong IGF2BP2 binding site; circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates, sequestering IGF2BP2 as a competing endogenous RNA and regulating STAT3 mRNA stability via IGF2BP2.\",\n      \"method\": \"eCLIP dataset mining, RIP assay, absolute copy number quantification, RNA sequencing, phase separation analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — eCLIP plus RIP, motif mutagenesis implied, copy number quantification, phase separation evidence, multiple orthogonal approaches\",\n      \"pmids\": [\"39041323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"High matrix stiffness in pancreatic cancer stabilizes IGF2BP2, which promotes sphingomyelin synthesis via SGMS2 upregulation; this pathway facilitates PD-L1 localization on membrane lipid rafts, enhancing immune evasion.\",\n      \"method\": \"MeRIP, RIP, RNA pull-down, single-cell RNA-sequencing, flow cytometry, multiplex IHC, humanized mouse models, PDAC organoids\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MeRIP, RIP, pulldown, in vivo humanized mouse model, multiple orthogonal methods; mechanistic axis (stiffness→IGF2BP2→SGMS2→lipid rafts→PD-L1) defined\",\n      \"pmids\": [\"40158738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM15 ubiquitinates IGF2BP2, which enhances IGF2BP2's function in phase separation and maintenance of TLR4 mRNA stability in pancreatic cancer; IGF2BP2 combines with TLR4 to inhibit its mRNA degradation.\",\n      \"method\": \"Transcriptomics, proteomics, Co-IP, ubiquitination assay, in vivo orthotopic mouse model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay plus in vivo model; TRIM15-IGF2BP2-TLR4 axis defined, single lab\",\n      \"pmids\": [\"38657551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP2 directly interacts with CD5L and CD36 mRNA (confirmed by RIP), stabilizing their expression; in osteoclastogenesis during periodontitis, IGF2BP2 regulates osteoclast differentiation via CD36 and CD5L, and its deficiency exacerbates early-stage inflammation but reduces osteoclast differentiation at later stages.\",\n      \"method\": \"RIP assay, AAV-mediated knockdown, ligature-induced periodontitis mouse model, overexpression rescue experiments\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirmed direct mRNA binding plus in vivo mouse model, rescue experiments, single lab\",\n      \"pmids\": [\"38193302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A circular RNA (circRNA-BISC) contains a 'CAC-linker-XGGX' motif that specifically binds IGF2BP2 (but not IGF2BP1 or IGF2BP3), inhibiting IGF2BP2-mediated translation enhancement of c-MYC mRNA and overcoming BETi resistance in TNBC.\",\n      \"method\": \"RIP-Seq, RNA immunoprecipitation, in vitro transcribed circRNA functional assays, cell and in vivo BETi-resistant TNBC models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP-Seq plus functional in vitro and in vivo validation, selectivity for IGF2BP2 over paralogs demonstrated, motif identified\",\n      \"pmids\": [\"40591591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 promotes YAP mRNA translation by recognizing its m6A modification in colorectal cancer; YAP subsequently promotes TEAD4 enrichment at the ErbB2 promoter to upregulate ErbB2 expression.\",\n      \"method\": \"RIP assay, m6A recognition, promoter enrichment assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP for m6A recognition plus functional rescue, single lab\",\n      \"pmids\": [\"34309973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP2 stabilizes m6A-modified FOSL1 mRNA in trophoblast cells in an IGF2BP2-dependent manner downstream of METTL3; elevated FOSL1 inhibits trophoblast invasion, contributing to fetal growth restriction.\",\n      \"method\": \"MeRIP-seq, RNA-seq, RIP assay, mRNA stability assay, in vivo FGR mouse model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP plus in vivo model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39565355\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2BP2 (IMP-2) is an m6A 'reader' RNA-binding protein that primarily recognizes N6-methyladenosine-modified mRNAs (and certain non-coding RNAs) at CDS or 3'UTR regions to stabilize them against degradation, and in some contexts (e.g., CDK6, EIF4A1, c-MYC) enhances their translation initiation by recruiting factors such as EIF4A1; its activity is regulated post-translationally by SIRT1-mediated acetylation (switching it between mRNA protection and degradation of specific targets like ATP6V1A), by SUMO1-mediated SUMOylation at K497/K505/K509 (blocking proteasomal degradation), by K139 ubiquitination (targeting it to autolysosomes), and by interactions with various lncRNAs and circRNAs that competitively block its ubiquitination or nucleate it into phase-separated condensates; its diverse m6A-dependent targets include SOX2, MYC, FEN1, Slug, PDX1, Fzd8, Pdx1, CDK6, NLRP3, TAB3, and many others, placing it at the intersection of post-transcriptional gene regulation, metabolism, immune function, and cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IGF2BP2 (IMP-2) is a sequence- and modification-specific RNA-binding protein that operates as a post-transcriptional regulatory hub, predominantly acting as an N6-methyladenosine (m6A) 'reader' that binds methylated transcripts at CDS, stop-codon, or 3'UTR regions to control their stability and translation [#0, #4, #7]. Its canonical output is target-mRNA protection: by recognizing m6A marks written by METTL3/METTL14, IGF2BP2 shields transcripts such as SOX2, FEN1, Slug, TAB3, and NLRP3 from degradation, thereby sustaining programs in cancer proliferation, EMT/metastasis, and inflammation [#0, #6, #7, #4, #25]. Beyond stabilization, IGF2BP2 can enhance translation initiation of m6A-modified targets — for CDK6 it does so without altering mRNA levels by recruiting EIF4A1, and it similarly drives translation of Pdx1, YAP, and c-MYC [#17, #12, #39, #38]. IGF2BP2 also operates as a negative regulator in defined contexts, recruiting the XRN2 nuclease or the CCR4-NOT deadenylase to destabilize specific transcripts (ATP6V1A, Fzd8) depending on its modification state and signaling input [#11, #29]. This functional switching is set by post-translational control: SIRT1-regulated acetylation toggles IGF2BP2 between mRNA protection and degradation [#11], SUMO1-mediated SUMOylation at K497/K505/K509 blocks proteasomal turnover [#10], and competing E3 ligases (FBW7/GSK3β, TRIM25, TRIM15) drive its ubiquitination and degradation [#18, #23, #36]. A large family of lncRNAs and circRNAs (LINRIS, circEZH2, circRHBDD1, LCAT1, circHIPK3, circRNA-BISC) bind IGF2BP2 to block its ubiquitination, nucleate it into phase-separated condensates, or competitively inhibit its translational activity [#1, #9, #23, #34, #38]. Genetically, IGF2BP2 is required for diverse developmental and metabolic programs, including zygotic genome activation at the 2-cell stage, pancreatic β-cell proliferation and insulin secretion, hematopoietic stem cell mitochondrial metabolism and self-renewal, and cardiomyocyte homeostasis, where its forced overexpression produces reversible dilated cardiomyopathy [#16, #12, #26, #28]. Earlier work established its role in muscle, where it binds PINCH-2, MURF-3, Myf5, and cyclin A2 transcripts and supports microtubule stabilization and myoblast function [#8, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established IGF2BP2 as a direct mRNA-binding regulator of protein output before its m6A-reader role was known, anchoring its function in cytoskeletal and motility control.\",\n      \"evidence\": \"Gel-shift (EMSA) and gain/loss-of-function in myoblasts identifying PINCH-2 and MURF-3 as bound transcripts and a requirement for microtubule stabilization\",\n      \"pmids\": [\"20956565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No m6A dependency tested at this stage\", \"Mechanism of stabilization vs translation control not distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed IGF2BP2 protects target mRNAs from miRNA-mediated decay and acts downstream of upstream regulators, broadening its role to competitive post-transcriptional control.\",\n      \"evidence\": \"shRNA/overexpression studies of RAF1 vs miR-195 in colorectal cancer, and rescue experiments placing IGF2BP2 downstream of HMGB2 for Myf5/cyclin A2 in myoblasts\",\n      \"pmids\": [\"27153315\", \"27672022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not always confirmed by orthogonal biophysical assays\", \"m6A involvement not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined IGF2BP2 as a bona fide m6A reader that stabilizes methylated transcripts and ncRNAs, establishing its central modern mechanism.\",\n      \"evidence\": \"MeRIP-seq, reciprocal RNA pull-down/RIP, and m6A-site mutagenesis for SOX2 mRNA (CDS) and DANCR lncRNA downstream of METTL3 in colorectal and pancreatic cancer\",\n      \"pmids\": [\"31230592\", \"31804607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether reading is stabilization or translation was not generalized\", \"Reader specificity over IGF2BP1/3 not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the first layer of IGF2BP2 protein-stability control by lncRNA, linking its abundance to glycolytic and developmental programs.\",\n      \"evidence\": \"RNA pull-down/RIP and ubiquitination assays showing LINRIS blocks K139 ubiquitination and autophagy-lysosome degradation; maternal conditional KO showing 2-cell arrest and IGF2 rescue\",\n      \"pmids\": [\"31791342\", \"31406667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the K139 E3 ligase not established here\", \"Direct targets driving ZGA arrest only partially defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved post-translational regulation of IGF2BP2 by SUMOylation and demonstrated m6A-dependent translational (not just stability) control of a physiological target.\",\n      \"evidence\": \"In vitro SUMOylation, Co-IP, and lysine mutagenesis (K497/K505/K509, SENP1 eraser); β-cell-specific Imp2 KO with RIP and m6A-dependent Pdx1 translation assays\",\n      \"pmids\": [\"34345216\", \"33705986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between SUMOylation and ubiquitination not quantified\", \"Generality of translational enhancement across targets unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established IGF2BP2 as a switchable regulator that can also degrade transcripts and recruit distinct effectors, and confirmed it as a druggable cancer target.\",\n      \"evidence\": \"SIRT1-acetylation/XRN2 recruitment switch on ATP6V1A; CCR4-NOT/mTOR-dependent Fzd8 degradation in MSCs; EIF4A1 recruitment for CDK6 translation; small-molecule CWI1-2 and biophysically validated inhibitors\",\n      \"pmids\": [\"36322753\", \"36219823\", \"37983610\", \"36306790\", \"35023719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants choosing protection vs degradation per transcript incompletely mapped\", \"Direct vs indirect effector recruitment not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the regulatory network controlling IGF2BP2 abundance through multiple E3 ligases and circRNA/lncRNA shields, and demonstrated feedback loops.\",\n      \"evidence\": \"Co-IP/ubiquitination assays for FBW7-GSK3β and TRIM25 (blocked by circRHBDD1); circEZH2 and circRUNX1 stabilization of IGF2BP2; SLC7A5-H3K4me3 positive feedback at the IGF2BP2 promoter\",\n      \"pmids\": [\"38281999\", \"39080693\", \"35773744\", \"36522683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of competing E3 ligases in vivo unknown\", \"Stoichiometry of circRNA shielding not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated genetic requirements of IGF2BP2 in stem-cell metabolism and cardiac homeostasis, showing dose- and reversibility-dependent pathology.\",\n      \"evidence\": \"Igf2bp2 KO mice showing impaired HSC oxidative metabolism and repopulation; inducible cardiomyocyte transgenic mice with reversible dilated cardiomyopathy\",\n      \"pmids\": [\"35231105\", \"38052926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mitochondrial/sarcomeric mRNA targets not fully enumerated\", \"Mechanism linking IGF2BP2 to mitochondrial fragmentation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined IGF2BP2 as a driver of immune evasion and inflammation across tissues, and established sequence-specific, paralog-selective circRNA antagonism via phase separation.\",\n      \"evidence\": \"MeRIP/RIP and in vivo models linking IGF2BP2 to NLRP3, PD-L1 (via SGMS2/lipid rafts and matrix stiffness), TLR4; circHIPK3 and circRNA-BISC motif-specific binding and condensate formation\",\n      \"pmids\": [\"38218935\", \"40158738\", \"38657551\", \"39041323\", \"40591591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of condensate assembly not solved\", \"Whether phase separation alters target selectivity globally unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IGF2BP2 integrates competing post-translational modifications, condensate formation, and m6A reading to deterministically select between stabilizing, degrading, or translationally enhancing a given transcript remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified structural model of the reader-effector interface\", \"Genome-wide rules predicting protection vs degradation are lacking\", \"Physiological hierarchy among acetylation, SUMOylation, and ubiquitination not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 7, 8, 17, 34]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [12, 17, 39, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 14, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 7, 11, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 6, 7, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 23, 25, 35]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EIF4A1\", \"XRN2\", \"CCR4-NOT\", \"SIRT1\", \"FBW7\", \"TRIM25\", \"TRIM15\", \"SENP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}