{"gene":"IMP3","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"IMP3 associates with IGF-II leader-3 and leader-4 mRNAs and H19 RNA (but not c-myc or beta-actin mRNAs) in vivo, and acts as a translational activator of IGF-II leader-3 mRNA; IMP3 knockdown reduced IGF-II protein levels without affecting mRNA levels and specifically suppressed translation of a chimeric IGF-II leader-3/luciferase reporter, demonstrating post-transcriptional translational activation.","method":"mRNP immunoprecipitation, siRNA knockdown, chimeric luciferase reporter assay in K562 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal mRNP-IP, reporter assay, and siRNA rescue with recombinant IGF-II, multiple orthogonal methods in single rigorous study","pmids":["15753088"],"is_preprint":false},{"year":2011,"finding":"IMP3 promotes cell survival after ionizing radiation by acting through the 5' UTR of IGF-II mRNA to enhance its translation; IMP3 knockdown increased IR-induced apoptosis and reduced IGF-II production, and exogenous recombinant IGF-II partially reversed these effects.","method":"siRNA knockdown, gene reporter assays with 5' UTR constructs, IR-induced apoptosis model in K562 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reporter assay with UTR constructs, siRNA rescue with recombinant ligand, multiple orthogonal methods","pmids":["21757716"],"is_preprint":false},{"year":2012,"finding":"IMP3 expression is induced transcriptionally by EGFR signaling via the MAPK pathway, and is repressed specifically by estrogen receptor β (ERβ) and its ligand 3βA-diol (but not ERα); ERβ also represses EGFR transcription via an imperfect estrogen response element in the EGFR promoter, providing an indirect mechanism for ERβ to suppress IMP3. IMP3 was shown to bind CD164 and MMP9 mRNAs, contributing to migration and invasion.","method":"siRNA/overexpression, promoter reporter assays, RNA immunoprecipitation, migration/invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays, RNA-IP, functional migration assays, multiple orthogonal methods in single study","pmids":["22266872"],"is_preprint":false},{"year":2013,"finding":"IMP3 binds BCRP (ABCG2) mRNA and regulates BCRP protein expression; depletion of IMP3 in triple-negative breast cancer cells increased sensitivity to doxorubicin and mitoxantrone (substrates of BCRP) but not taxol, establishing IMP3 as a regulator of chemoresistance through BCRP mRNA binding.","method":"siRNA knockdown, RNA immunoprecipitation, drug sensitivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA-IP demonstrating direct binding, functional drug sensitivity assays, multiple orthogonal methods","pmids":["23539627"],"is_preprint":false},{"year":2013,"finding":"IMP3 is enriched in the nucleus of human cancer cells (compared to IMP1 and IMP2), where it binds CCND1, CCND3, and CCNG1 mRNAs and is required for their expression; IMP3 knockdown caused dramatic loss of cyclins D1, D3, and G1 protein and G1 cell cycle arrest. Nuclear localization depends on the protein partner HNRNPM, and cytoplasmic retention of IMP3 abolishes cyclin regulation.","method":"siRNA knockdown, in vivo and in vitro RNA binding assays, subcellular fractionation, cell cycle analysis across six cancer cell lines","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cancer cell lines, in vitro RNA binding, subcellular fractionation with functional consequence, multiple orthogonal methods","pmids":["23812426"],"is_preprint":false},{"year":2014,"finding":"IMP3 ribonucleoprotein granules function as cytoplasmic 'safe houses' that protect let-7 target mRNAs (including HMGA2 and LIN28B) from miRNA-directed decay; IMP3-containing bodies are depleted of Ago1-4 and miRNAs, and IMP3 dose-dependently increases HMGA2 mRNA. Removal of let-7 target sites or let-7 antagomiRs abolishes IMP3-dependent stabilization.","method":"Transcriptome analysis, cytoplasmic granule fractionation, antagomiR experiments, HMGA2 3' UTR deletion constructs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (granule fractionation, antagomiR, UTR mutants), mechanistically defined exclusion of miRNA machinery","pmids":["24703842"],"is_preprint":false},{"year":2015,"finding":"IMP3 binds SNAI2 (SLUG) mRNA at the 5' UTR and regulates SLUG expression; SLUG in turn transcriptionally activates SOX2, promoting breast cancer stem cell self-renewal and tumor initiation in triple-negative breast cancer. IMP3 does not bind SOX2 mRNA directly.","method":"RNA immunoprecipitation, 5' UTR reporter assays, siRNA/overexpression, tumor initiation assays in xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-IP, 5'UTR reporter, in vivo xenograft, multiple orthogonal methods","pmids":["25982283"],"is_preprint":false},{"year":2016,"finding":"IMP3 directly interacts with ULBP2 mRNA, leading to its destabilization and reduced ULBP2 surface expression in human cell lines, thereby impairing NK cell recognition. IMP3 also indirectly targets MICB through a mechanistically distinct pathway.","method":"RNA immunoprecipitation, mRNA stability assays, NK cell cytotoxicity assays, flow cytometry for surface expression","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA-IP, mRNA stability, functional NK killing assay, multiple orthogonal methods","pmids":["26982091"],"is_preprint":false},{"year":2016,"finding":"IMP3 and its partners ILF3/NF90 and PTBP1 bind to the 3' UTRs of cyclin D1 and D3 mRNAs and protect them from translational repression induced by AGO2/GW182-dependent miRNA pathway; upon IMP3 knockdown, cyclin mRNAs remain polysome-associated but are not translated, indicating regulation at the translational level.","method":"siRNA knockdown, polysome fractionation, 3' UTR binding assays, co-immunoprecipitation","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — polysome fractionation and co-IP in single lab, mechanistic follow-up of prior work","pmids":["27840950"],"is_preprint":false},{"year":2016,"finding":"IMP3 forms circRNA-protein complexes (circRNPs) with a defined subset of circular RNAs in mammalian cells; glycerol gradient centrifugation revealed circRNPs of distinct sizes, and RNA-seq of IMP3-co-immunoprecipitated RNA identified specific IMP3-associated circRNAs. No evidence was found for efficient translation of these abundant circRNAs.","method":"Glycerol gradient centrifugation, co-immunoprecipitation of RNA, polysome gradient fractionation, RNA-seq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (gradient sedimentation, co-IP, RNA-seq) in single study; negative result on translation is informative","pmids":["27510448"],"is_preprint":false},{"year":2017,"finding":"IMP3 promotes glioma cell migration by directly binding p65 (RELA) mRNA 3' UTR and enhancing its translation (polysome association increased without change in transcript level); exogenous p65 from a 3'UTR-less construct rescued migration in IMP3-silenced cells. A positive feedback loop exists between IMP3 and NF-κB/p65, as IMP3 is transcriptionally activated by NF-κB.","method":"RNA immunoprecipitation-PCR, UV crosslinking with in vitro transcribed RNA, 3'UTR luciferase reporter (wild-type vs. mutant), polysome profiling, migration assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — UV crosslinking reconstitution, mutant UTR reporter, polysome profiling, and functional rescue, multiple orthogonal methods","pmids":["28465487"],"is_preprint":false},{"year":2017,"finding":"IMP2 and IMP3 cooperate to promote TNBC metastasis by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT/CNOT1 complex, suppressing PR expression and thereby downregulating miR-200a; this forms a double-negative feedback loop.","method":"siRNA knockdown/overexpression, co-immunoprecipitation with CNOT1, mRNA stability assays, migration/invasion assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with CNOT1, mRNA stability, functional assays in single lab","pmids":["29217458"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of IMP3 RRM12 reveals that both RRM domains adopt canonical RRM topology; only RRM1 contacts RNA and recognizes a dinucleotide sequence; the spatial orientation of RRM1 relative to RRM2 is unique compared to other tandem RRM structures.","method":"X-ray crystallography, biochemical RNA binding characterization","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical validation in single rigorous study","pmids":["30135093"],"is_preprint":false},{"year":2018,"finding":"IMP3 stabilizes WNT5B mRNA indirectly by repressing miR-145-5p (which targets WNT5B), leading to TAZ activation via alternative WNT signaling. IMP3 also facilitates SLUG transcription (required for TAZ nuclear localization) through a WNT5B-dependent mechanism, integrating Hippo and alternative WNT signaling pathways.","method":"mRNA stability assays, miRNA manipulation, siRNA/overexpression, reporter assays, breast cancer stem cell functional assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability, miRNA manipulation, multiple pathway readouts in single lab","pmids":["29847788"],"is_preprint":false},{"year":2019,"finding":"IMP3 uses a combinatorial RNA recognition code involving all six RNA-binding domains (four KH and two RRM) to recognize a cluster of up to five distinct CA-rich and GGC-core RNA elements appropriately spaced across a >100 nucleotide target region; single-domain SELEX-seq, iCLIP, structural biology, and functional validation together define the RNA-binding specificity and RNP topology.","method":"Single-domain SELEX-seq, iCLIP, motif-spacing analysis, structural biology, functional reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-level SELEX, structural biology, in vivo iCLIP, functional validation; multiple orthogonal methods, highly systematic","pmids":["31118463"],"is_preprint":false},{"year":2015,"finding":"IL-18 signaling induces shuttling of IMP3 and HuR from nucleus to cytoplasm and facilitates their interaction; the IMP3-HuR complex then binds the 3' UTR of COX-2 mRNA to stabilize it, contributing to chemoresistance in AML cells. JNK and/or ERK1/2 regulate HuR nucleocytoplasmic shuttling in this pathway.","method":"Co-immunoprecipitation, RNA immunoprecipitation, subcellular fractionation, mRNA stability assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP, co-IP, fractionation, single lab with multiple methods","pmids":["26342105"],"is_preprint":false},{"year":2015,"finding":"RELB interacts with IMP3 and LIN28A in human pluripotent stem cells; these interactions control mRNA levels and protein expression of IGF2 and key cell-cycle genes; after stress, IMP3, LIN28, and RELB co-localize in stress granules.","method":"Co-immunoprecipitation, stress granule co-localization (immunofluorescence), quantitative PCR and western blot","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and localization data, single lab, limited functional follow-up on IMP3 specifically","pmids":["25794352"],"is_preprint":false},{"year":2020,"finding":"IMP3 directly binds the 3' UTR of HK2 mRNA (hexokinase 2) to stabilize it; circCDKN2B-AS1 acts as a sponge for IMP3 protein, sequestering it and thereby modulating how much IMP3 is available to bind HK2 mRNA 3' UTR. Mutant circCDKN2B-AS1 lacking the IMP3 binding site lacks this effect.","method":"RNA pull-down, RNA immunoprecipitation, actinomycin-D mRNA stability assay, binding-site mutagenesis, western blot","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down, RIP, mRNA stability, mutagenesis confirming binding site; single lab","pmids":["33308298"],"is_preprint":false},{"year":2020,"finding":"IMP3 promotes prostate cancer progression by upregulating SMURF1 expression, which in turn facilitates PTEN ubiquitination and degradation, activating the PI3K/AKT/mTOR signaling pathway; SMURF1 knockdown rescues the proliferative and survival phenotypes induced by IMP3 overexpression.","method":"Immunoprecipitation/ubiquitination assay, siRNA/overexpression, western blot for PI3K/AKT/mTOR pathway components, in vivo tumor formation","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-ubiquitination, pathway epistasis by SMURF1 rescue, in vivo validation; single lab","pmids":["32938489"],"is_preprint":false},{"year":2021,"finding":"IMP3 directly binds the 3' UTR of MEKK1 mRNA to stabilize it, promoting MEKK1 expression and sequentially activating MEK1/ERK signaling in colorectal cancer; IMP3 conditional knockout mice show decreased MEKK1 expression and reduced colorectal tumors in an AOM/DSS model.","method":"RNA immunoprecipitation, luciferase 3'UTR reporter assay, RNA-sequencing, conditional IMP3 knockout mouse, western blot","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-IP, 3'UTR reporter, in vivo knockout mouse model, RNA-seq, multiple orthogonal methods","pmids":["34154626"],"is_preprint":false},{"year":2013,"finding":"In yeast/zebrafish model: Imp3 (as part of the Mpp10-Imp3-Imp4 complex) unfolds both the box A/A' stem in U3 snoRNA and helix 1 (H1) in the 18S region of pre-rRNA to promote U3-18S duplex formation required for small subunit processome cleavages at A0 and A1 sites; Imp3 binding alone provides sufficient energy for this unfolding, while Imp4 destabilizes the duplex to aid U3 release.","method":"Chemical modification probing, ribonuclease accessibility assay, in vitro reconstitution of U3-18S hybridization","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with chemical probing, mechanistic differentiation of Imp3 vs Imp4 roles; rigorous biochemical study","pmids":["23980203"],"is_preprint":false},{"year":2019,"finding":"In zebrafish model: Sas10 determines the nucleolar localization of the Mpp10-Imp3-Imp4 complex; Sas10 protects Mpp10 from Capn3-mediated cleavage by masking the Capn3-recognition site, while Def interacts with Sas10 to form the Def-Sas10-Mpp10 complex that facilitates Capn3-mediated Mpp10 cleavage. Mpp10, but not Sas10, is a target of the Def-Capn3 degradation pathway.","method":"Zebrafish genetics, co-immunoprecipitation, nucleolar localization studies, protein stability assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, localization experiments, genetic model in zebrafish; single lab","pmids":["30773582"],"is_preprint":false},{"year":2014,"finding":"IMP3 binds SLUG (SNAI2) mRNA directly (confirmed by ribo-immunoprecipitation qPCR) and regulates SLUG expression; IMP3 overexpression induces EMT markers (reduced E-cadherin, increased Slug and vimentin); knockdown of SLUG in IMP3-overexpressing cells reverses migration and invasion, and SLUG overexpression rescues invasion in IMP3-depleted cells, establishing SLUG as a functional downstream target of IMP3 in EMT.","method":"RNA immunoprecipitation-qPCR, siRNA knockdown/overexpression, Transwell migration/invasion assays, western blot for EMT markers","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP, epistasis rescue experiment, functional migration assay; single lab","pmids":["25031719"],"is_preprint":false},{"year":2015,"finding":"IMP3 knockdown in pancreatic ductal adenocarcinoma cells significantly decreased cell motility, invasion, and extracellular matrix adhesion; IMP3-depleted cells showed reduced CD44 protein levels, decreased KIF11 mRNA, and reduced downstream RhoA signaling, indicating IMP3 modulates cytoskeletal organization via RhoA pathway.","method":"siRNA knockdown, Transwell migration/invasion assay, matrix adhesion assay, western blot for RhoA pathway","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional knockdown assays with pathway readout, replicated across multiple PDAC cell lines","pmids":["25886367"],"is_preprint":false},{"year":2015,"finding":"IMP3 overexpression activates the NF-κB pathway in renal cell carcinoma cells, and pharmacological inhibition of NF-κB abrogates IMP3-promoted cell migration, placing IMP3 upstream of NF-κB in promoting RCC cell migration.","method":"Stable IMP3 overexpression, siRNA knockdown, RNA-seq, Transwell migration assay, NF-κB inhibition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis via inhibitor, RNA-seq for global targets, functional migration assay; single lab","pmids":["25919292"],"is_preprint":false},{"year":2024,"finding":"IMP3 knockdown in HeLa cervical cancer cells significantly reduced cell migration without altering cell proliferation, demonstrating a specific role of IMP3 in cell motility regulation.","method":"siRNA knockdown, scratch/wound-healing migration assay, proliferation assay","journal":"The American journal of surgical pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay, single cell line, no mechanistic pathway identified","pmids":["21997684"],"is_preprint":false}],"current_model":"IMP3 (IGF2BP3) is a multidomain RNA-binding protein (two RRM and four KH domains) that uses a combinatorial recognition code—involving all six RNA-binding domains contacting clustered CA-rich and GGC-core motifs across >100 nucleotides—to bind and regulate specific target mRNAs at multiple levels: it acts as a translational activator (IGF-II, p65/RELA mRNAs via 5' UTR or polysome recruitment), stabilizes target mRNAs by sequestering them in cytoplasmic RNP granules that exclude the miRNA/AGO2 machinery (protecting HMGA2, LIN28B, and other let-7 targets from miRNA-directed decay), destabilizes select mRNAs (ULBP2, PR), and in the nucleus (where its localization depends on HNRNPM) regulates translation of cyclin D1, D3, and G1 mRNAs while protecting them from AGO2/GW182-mediated repression; through these mechanisms IMP3 promotes cell proliferation (via IGF-II and cyclin D1/D3), migration and invasion (via SLUG/EMT, RhoA, NF-κB, and p65), cancer stem cell self-renewal (via SLUG-SOX2 axis and TAZ/WNT5B), chemoresistance (via BCRP/ABCG2 and COX-2 mRNA stabilization), and tumor immune evasion (via ULBP2 mRNA destabilization reducing NK cell recognition), with upstream regulation by EGFR/MAPK signaling (inducing IMP3) and ERβ (repressing IMP3 indirectly via EGFR suppression); in ribosome biogenesis, Imp3 unfolds conserved stem structures in both U3 snoRNA and pre-rRNA 18S helix 1 to promote U3-18S duplex formation essential for small subunit processome cleavage."},"narrative":{"mechanistic_narrative":"IMP3 (IGF2BP3) is a multidomain RNA-binding protein that post-transcriptionally controls the fate of specific target mRNAs to drive cell proliferation, migration, and tumor-associated programs [PMID:15753088, PMID:23812426, PMID:25982283]. It engages targets through a combinatorial recognition code in which all six RNA-binding domains (four KH and two RRM) contact clustered CA-rich and GGC-core elements spaced across a >100-nucleotide region [PMID:31118463]; structurally, only RRM1 of the tandem RRM12 module contacts RNA in a uniquely oriented arrangement [PMID:30135093]. Mechanistically IMP3 operates at multiple levels: it acts as a translational activator, enhancing translation of IGF-II via its 5' UTR and of p65/RELA mRNA via increased polysome association [PMID:15753088, PMID:21757716, PMID:28465487]; it stabilizes target mRNAs by sequestering them in cytoplasmic RNP granules depleted of the Ago/miRNA machinery, protecting let-7 targets such as HMGA2 and LIN28B from miRNA-directed decay [PMID:24703842]; and it destabilizes select transcripts, including ULBP2 to impair NK-cell recognition and PR mRNA via recruitment of the CCR4-NOT/CNOT1 deadenylase complex [PMID:26982091, PMID:29217458]. In the nucleus, where its localization depends on the partner HNRNPM, IMP3 binds and is required for expression of cyclin D1, D3, and G1 mRNAs, protecting cyclin D mRNAs from AGO2/GW182-mediated translational repression together with ILF3/NF90 and PTBP1 [PMID:23812426, PMID:27840950]. Through these activities IMP3 promotes cancer stem-cell self-renewal via a SLUG/SNAI2-SOX2 axis and TAZ/WNT5B signaling [PMID:25982283, PMID:29847788, PMID:25031719], chemoresistance via BCRP/ABCG2 and COX-2 mRNA stabilization [PMID:23539627, PMID:26342105], and migration/invasion via NF-κB, RhoA, and MEKK1/ERK signaling [PMID:34154626, PMID:25886367, PMID:25919292], with upstream induction by EGFR/MAPK signaling and repression by ERβ [PMID:22266872]. Separately, in ribosome biogenesis IMP3 (as part of the Mpp10-Imp3-Imp4 complex) unfolds conserved stem structures in U3 snoRNA and pre-rRNA 18S helix 1 to promote U3-18S duplex formation required for small-subunit processome cleavage [PMID:23980203, PMID:30773582].","teleology":[{"year":2005,"claim":"Established IMP3 as a sequence-specific translational activator rather than a transcriptional regulator, defining its core post-transcriptional mode of action on IGF-II mRNA.","evidence":"mRNP immunoprecipitation, siRNA knockdown, and chimeric leader-3/luciferase reporter in K562 cells","pmids":["15753088"],"confidence":"High","gaps":["Did not map the RNA element or domains required for binding","Limited to IGF-II among possible targets"]},{"year":2011,"claim":"Connected IMP3-driven IGF-II translation to a physiological survival outcome, showing IMP3 promotes survival after ionizing radiation through 5' UTR-dependent IGF-II translation.","evidence":"5' UTR reporter constructs, siRNA knockdown, and recombinant IGF-II rescue in an IR-apoptosis model","pmids":["21757716"],"confidence":"High","gaps":["Mechanism by which IMP3 enhances 5' UTR translation not resolved","Single cell-line context"]},{"year":2012,"claim":"Defined upstream control of IMP3, showing it is induced by EGFR/MAPK signaling and repressed by ERβ, embedding IMP3 in oncogenic signaling networks.","evidence":"Promoter reporter assays, RNA-IP, siRNA/overexpression, and migration/invasion assays","pmids":["22266872"],"confidence":"High","gaps":["Direct transcription factor binding to the IMP3 promoter not fully mapped","CD164/MMP9 regulation mechanism not detailed"]},{"year":2013,"claim":"Extended IMP3 targets to drug-resistance and cell-cycle machinery: it binds BCRP/ABCG2 mRNA to confer chemoresistance and is nuclear-enriched where it is required for cyclin D1/D3/G1 expression and G1 progression.","evidence":"RNA-IP, drug sensitivity assays, subcellular fractionation, and cell cycle analysis across multiple cancer lines; nuclear localization shown to depend on HNRNPM","pmids":["23539627","23812426"],"confidence":"High","gaps":["How HNRNPM directs IMP3 nuclear import mechanistically unresolved","Whether cyclin regulation is at stability or translation not distinguished here"]},{"year":2014,"claim":"Revealed a stabilization mechanism distinct from translational activation: IMP3 granules act as 'safe houses' that exclude the miRNA/Ago machinery to protect let-7 target mRNAs from decay.","evidence":"Transcriptome analysis, cytoplasmic granule fractionation, antagomiR experiments, and HMGA2 3' UTR deletion constructs; plus RNA-IP/EMT rescue defining SLUG as a downstream target","pmids":["24703842","25031719"],"confidence":"High","gaps":["What nucleates IMP3 granule assembly is unknown","How granules physically exclude Ago not defined"]},{"year":2015,"claim":"Linked IMP3 to stem-cell self-renewal and stress responses, defining a SLUG-SOX2 axis for breast cancer stem cells and stress-granule co-localization with LIN28/RELB partners.","evidence":"RNA-IP, 5' UTR reporters, xenograft tumor-initiation assays; co-IP and stress-granule immunofluorescence; NF-κB inhibition and migration assays in RCC; IL-18-induced IMP3-HuR/COX-2 stabilization in AML","pmids":["25982283","25794352","25919292","26342105","25886367"],"confidence":"Medium","gaps":["Several mechanisms rest on single-lab co-IP or inhibitor epistasis","Direct versus indirect target distinctions not always established"]},{"year":2016,"claim":"Diversified the regulatory repertoire to include mRNA destabilization and partner-assisted control: IMP3 destabilizes ULBP2 to evade NK cells, protects cyclin D mRNAs with ILF3/PTBP1, and assembles defined circRNP complexes.","evidence":"RNA-IP, mRNA stability and NK cytotoxicity assays; polysome fractionation and co-IP; glycerol-gradient/RNA-seq circRNP characterization","pmids":["26982091","27840950","27510448"],"confidence":"Medium","gaps":["Determinants of stabilize-versus-destabilize outcome unknown","Functional role of IMP3-bound circRNAs unresolved"]},{"year":2017,"claim":"Showed IMP3 drives migration through reinforcing feedback loops: it enhances p65/RELA translation in a positive loop with NF-κB, and cooperates with IMP2 to destabilize PR mRNA via CCR4-NOT.","evidence":"UV crosslinking, mutant 3' UTR reporters, polysome profiling, and rescue for p65; co-IP with CNOT1 and stability assays for PR","pmids":["28465487","29217458"],"confidence":"Medium","gaps":["CNOT1 recruitment mechanism by IMP3 not structurally defined","p65 loop validated mainly in glioma context"]},{"year":2018,"claim":"Provided the molecular and structural basis for IMP3 specificity, defining a six-domain combinatorial recognition code and a unique tandem-RRM architecture.","evidence":"Single-domain SELEX-seq, iCLIP, motif-spacing analysis, and crystallography of RRM12","pmids":["31118463","30135093"],"confidence":"High","gaps":["Full-length six-domain RNP structure on a native target not solved","How recognition code dictates stabilize-vs-destabilize fate not addressed"]},{"year":2020,"claim":"Expanded IMP3 targets into metabolic and signaling regulators and showed its activity is itself tunable by circRNA sponging.","evidence":"RNA pull-down, RIP, actinomycin-D stability assays, and binding-site mutagenesis for HK2/circCDKN2B-AS1; IP-ubiquitination and SMURF1 rescue for the PTEN-PI3K/AKT axis","pmids":["33308298","32938489"],"confidence":"Medium","gaps":["Single-lab validation of each axis","Generality of circRNA sponging of IMP3 unknown"]},{"year":2021,"claim":"Provided in vivo genetic confirmation of IMP3-driven tumorigenesis through MEKK1/ERK signaling in colorectal cancer.","evidence":"RNA-IP, 3' UTR luciferase reporter, RNA-seq, and conditional IMP3 knockout in an AOM/DSS mouse model","pmids":["34154626"],"confidence":"High","gaps":["Tissue specificity of MEKK1 stabilization not explored","Relationship to other IMP3 migration pathways not integrated"]},{"year":2013,"claim":"Defined a mechanistically separate, conserved role for Imp3 in ribosome biogenesis as an RNA-structure chaperone unfolding U3 snoRNA and pre-rRNA stems to enable processome cleavage.","evidence":"Chemical modification probing, ribonuclease accessibility, and in vitro reconstitution of U3-18S hybridization in yeast/zebrafish; zebrafish genetics defining Sas10/Def-dependent nucleolar localization and Mpp10 stability","pmids":["23980203","30773582"],"confidence":"High","gaps":["Whether this processome role exists in human cells alongside mRNA functions not addressed in this corpus","How the same protein partitions between nucleolar and cytoplasmic mRNA roles unknown"]},{"year":null,"claim":"It remains unresolved what molecular features of a bound transcript determine whether IMP3 stabilizes, destabilizes, or translationally activates it, and how IMP3 partitions between its mRNA-regulatory and ribosome-biogenesis functions.","evidence":"No single discovery in the corpus reconciles the divergent regulatory outcomes or the dual nucleolar/cytoplasmic roles","pmids":[],"confidence":"Low","gaps":["No unifying rule linking RNA recognition code to regulatory outcome","No structure of full-length IMP3 on a native target","Crosstalk between processome and mRNA roles uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,5,7,12,14]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,8,10]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,11,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,15]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,7,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,19,24]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[20,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,18,19]}],"complexes":["Mpp10-Imp3-Imp4 complex","IMP3-HuR complex"],"partners":["HNRNPM","ILF3","PTBP1","CNOT1","HUR","LIN28A","RELB","IMP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TCT8","full_name":"Signal peptide peptidase-like 2A","aliases":["Intramembrane protease 3","IMP-3","Presenilin-like protein 2"],"length_aa":520,"mass_kda":58.1,"function":"Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing (PubMed:16829951, PubMed:16829952, PubMed:17557115, PubMed:17965014). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD) (PubMed:17557115). Essential for degradation of the invariant chain CD74 that plays a central role in the function of antigen-presenting cells in the immune system (By similarity). Plays a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852)","subcellular_location":"Late endosome membrane; Lysosome membrane; Membrane","url":"https://www.uniprot.org/uniprotkb/Q8TCT8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IMP3","classification":"Common 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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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IMP3"},"hgnc":{"alias_symbol":["FLJ10968","BRMS2"],"prev_symbol":["MRPS4","C15orf12"]},"alphafold":{"accession":"Q8TCT8","domains":[{"cath_id":"3.50.30.30","chopping":"27-162","consensus_level":"high","plddt":84.8936,"start":27,"end":162},{"cath_id":"-","chopping":"171-494","consensus_level":"high","plddt":84.1935,"start":171,"end":494}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCT8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCT8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCT8-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IMP3","jax_strain_url":"https://www.jax.org/strain/search?query=IMP3"},"sequence":{"accession":"Q8TCT8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TCT8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TCT8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCT8"}},"corpus_meta":[{"pmid":"15753088","id":"PMC_15753088","title":"The 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sensitive and highly specific for pancreatic ductal adenocarcinoma.","date":"2018","source":"Journal of the American Society of Cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/31043302","citation_count":15,"is_preprint":false},{"pmid":"23980203","id":"PMC_23980203","title":"Imp3 unfolds stem structures in pre-rRNA and U3 snoRNA to form a duplex essential for small subunit processing.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23980203","citation_count":14,"is_preprint":false},{"pmid":"32273198","id":"PMC_32273198","title":"Utility of pVHL, maspin, IMP3, S100P and Ki67 in the distinction of autoimmune pancreatitis from pancreatic ductal adenocarcinoma.","date":"2020","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/32273198","citation_count":14,"is_preprint":false},{"pmid":"30498299","id":"PMC_30498299","title":"Diagnostic Value of S100p, IMP3, Maspin, and pVHL in the Differantial Diagnosis of Pancreatic Ductal Adenocarcinoma and Normal/chronic Pancreatitis in Fine Needle Aspiration Biopsy.","date":"2018","source":"Journal of cytology","url":"https://pubmed.ncbi.nlm.nih.gov/30498299","citation_count":14,"is_preprint":false},{"pmid":"26874572","id":"PMC_26874572","title":"Diagnostic value of IMP3 and mesothelin in differentiating pancreatic ductal adenocarcinoma from chronic pancreatitis.","date":"2016","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/26874572","citation_count":14,"is_preprint":false},{"pmid":"25183049","id":"PMC_25183049","title":"Expression and clinical significance of IMP3 in microdissected premalignant and malignant pancreatic lesions.","date":"2014","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/25183049","citation_count":13,"is_preprint":false},{"pmid":"28485999","id":"PMC_28485999","title":"IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.","date":"2017","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28485999","citation_count":13,"is_preprint":false},{"pmid":"23806529","id":"PMC_23806529","title":"Oncofetal protein IMP3: a new diagnostic biomarker for laryngeal carcinoma.","date":"2013","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23806529","citation_count":13,"is_preprint":false},{"pmid":"23618832","id":"PMC_23618832","title":"The utility of PAX8 and IMP3 immunohistochemical stains in the differential diagnosis of benign, premalignant, and malignant endocervical glandular lesions.","date":"2013","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23618832","citation_count":13,"is_preprint":false},{"pmid":"22495359","id":"PMC_22495359","title":"IMP3, NESP55, TTF-1 and CDX2 serve as an immunohistochemical panel in the distinction among small-cell carcinoma, gastrointestinal carcinoid, and pancreatic endocrine tumor metastasized to the liver.","date":"2012","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/22495359","citation_count":13,"is_preprint":false},{"pmid":"21809995","id":"PMC_21809995","title":"The oncofetal protein IMP3: a novel molecular marker to predict aggressive meningioma.","date":"2011","source":"Archives of pathology & laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21809995","citation_count":13,"is_preprint":false},{"pmid":"26386725","id":"PMC_26386725","title":"EGF enhances low-invasive cancer cell invasion by promoting IMP-3 expression.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26386725","citation_count":13,"is_preprint":false},{"pmid":"36937398","id":"PMC_36937398","title":"Association of circulating tumor cells and IMP3 expression with metastasis of osteosarcoma.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36937398","citation_count":12,"is_preprint":false},{"pmid":"27840950","id":"PMC_27840950","title":"IMP-3 protects the mRNAs of cyclins D1 and D3 from GW182/AGO2-dependent translational repression.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27840950","citation_count":12,"is_preprint":false},{"pmid":"32293476","id":"PMC_32293476","title":"IGF2BP3 (IMP3) expression in angiosarcoma, epithelioid hemangioendothelioma, and benign vascular lesions.","date":"2020","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32293476","citation_count":11,"is_preprint":false},{"pmid":"26948096","id":"PMC_26948096","title":"Expression of insulin-like growth factor II mRNA binding protein 3 (IMP3) in enchondroma and chondrosarcoma.","date":"2016","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/26948096","citation_count":11,"is_preprint":false},{"pmid":"25038792","id":"PMC_25038792","title":"IMP3 as a cytoplasmic biomarker for early serous tubal carcinogenesis.","date":"2014","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/25038792","citation_count":10,"is_preprint":false},{"pmid":"19898970","id":"PMC_19898970","title":"Analysis of IMP3 expression in normal and neoplastic human pituitary tissues.","date":"2010","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19898970","citation_count":10,"is_preprint":false},{"pmid":"27839709","id":"PMC_27839709","title":"The role of S100P and IMP3 in the cytologic diagnosis of pancreatic adenocarcinoma.","date":"2016","source":"Journal of the Egyptian National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/27839709","citation_count":10,"is_preprint":false},{"pmid":"37140546","id":"PMC_37140546","title":"Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components.","date":"2023","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37140546","citation_count":10,"is_preprint":false},{"pmid":"25695077","id":"PMC_25695077","title":"The oncofetal protein IMP3: a novel grading tool and predictor of poor clinical outcome in human gliomas.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25695077","citation_count":10,"is_preprint":false},{"pmid":"28804555","id":"PMC_28804555","title":"IMP3 is upregulated in primary ovarian mucinous carcinoma and promotes tumor progression.","date":"2017","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/28804555","citation_count":10,"is_preprint":false},{"pmid":"25740666","id":"PMC_25740666","title":"Expression of IMP3 and IGF2 in giant cell tumor of spine is associated with tumor recurrence and angiogenesis.","date":"2015","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/25740666","citation_count":10,"is_preprint":false},{"pmid":"25794352","id":"PMC_25794352","title":"RELB Alters Proliferation of Human Pluripotent Stem Cells via IMP3- and LIN28-Mediated Modulation of the Expression of IGF2 and Other Cell-Cycle Regulators.","date":"2015","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/25794352","citation_count":10,"is_preprint":false},{"pmid":"34503117","id":"PMC_34503117","title":"IMP3 Protein Overexpression Is Linked to Unfavorable Outcome in Laryngeal Squamous Cell Carcinoma.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34503117","citation_count":9,"is_preprint":false},{"pmid":"24605891","id":"PMC_24605891","title":"Differential expression of IMP3 between male and female mature teratomas--immunohistochemical evidence of malignant nature.","date":"2014","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24605891","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56066,"output_tokens":6610,"usd":0.133674,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15607,"output_tokens":4771,"usd":0.098655,"stage2_stop_reason":"end_turn"},"total_usd":0.232329,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"IMP3 associates with IGF-II leader-3 and leader-4 mRNAs and H19 RNA (but not c-myc or beta-actin mRNAs) in vivo, and acts as a translational activator of IGF-II leader-3 mRNA; IMP3 knockdown reduced IGF-II protein levels without affecting mRNA levels and specifically suppressed translation of a chimeric IGF-II leader-3/luciferase reporter, demonstrating post-transcriptional translational activation.\",\n      \"method\": \"mRNP immunoprecipitation, siRNA knockdown, chimeric luciferase reporter assay in K562 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal mRNP-IP, reporter assay, and siRNA rescue with recombinant IGF-II, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"15753088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IMP3 promotes cell survival after ionizing radiation by acting through the 5' UTR of IGF-II mRNA to enhance its translation; IMP3 knockdown increased IR-induced apoptosis and reduced IGF-II production, and exogenous recombinant IGF-II partially reversed these effects.\",\n      \"method\": \"siRNA knockdown, gene reporter assays with 5' UTR constructs, IR-induced apoptosis model in K562 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reporter assay with UTR constructs, siRNA rescue with recombinant ligand, multiple orthogonal methods\",\n      \"pmids\": [\"21757716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IMP3 expression is induced transcriptionally by EGFR signaling via the MAPK pathway, and is repressed specifically by estrogen receptor β (ERβ) and its ligand 3βA-diol (but not ERα); ERβ also represses EGFR transcription via an imperfect estrogen response element in the EGFR promoter, providing an indirect mechanism for ERβ to suppress IMP3. IMP3 was shown to bind CD164 and MMP9 mRNAs, contributing to migration and invasion.\",\n      \"method\": \"siRNA/overexpression, promoter reporter assays, RNA immunoprecipitation, migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays, RNA-IP, functional migration assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22266872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IMP3 binds BCRP (ABCG2) mRNA and regulates BCRP protein expression; depletion of IMP3 in triple-negative breast cancer cells increased sensitivity to doxorubicin and mitoxantrone (substrates of BCRP) but not taxol, establishing IMP3 as a regulator of chemoresistance through BCRP mRNA binding.\",\n      \"method\": \"siRNA knockdown, RNA immunoprecipitation, drug sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP demonstrating direct binding, functional drug sensitivity assays, multiple orthogonal methods\",\n      \"pmids\": [\"23539627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IMP3 is enriched in the nucleus of human cancer cells (compared to IMP1 and IMP2), where it binds CCND1, CCND3, and CCNG1 mRNAs and is required for their expression; IMP3 knockdown caused dramatic loss of cyclins D1, D3, and G1 protein and G1 cell cycle arrest. Nuclear localization depends on the protein partner HNRNPM, and cytoplasmic retention of IMP3 abolishes cyclin regulation.\",\n      \"method\": \"siRNA knockdown, in vivo and in vitro RNA binding assays, subcellular fractionation, cell cycle analysis across six cancer cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cancer cell lines, in vitro RNA binding, subcellular fractionation with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"23812426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IMP3 ribonucleoprotein granules function as cytoplasmic 'safe houses' that protect let-7 target mRNAs (including HMGA2 and LIN28B) from miRNA-directed decay; IMP3-containing bodies are depleted of Ago1-4 and miRNAs, and IMP3 dose-dependently increases HMGA2 mRNA. Removal of let-7 target sites or let-7 antagomiRs abolishes IMP3-dependent stabilization.\",\n      \"method\": \"Transcriptome analysis, cytoplasmic granule fractionation, antagomiR experiments, HMGA2 3' UTR deletion constructs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (granule fractionation, antagomiR, UTR mutants), mechanistically defined exclusion of miRNA machinery\",\n      \"pmids\": [\"24703842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IMP3 binds SNAI2 (SLUG) mRNA at the 5' UTR and regulates SLUG expression; SLUG in turn transcriptionally activates SOX2, promoting breast cancer stem cell self-renewal and tumor initiation in triple-negative breast cancer. IMP3 does not bind SOX2 mRNA directly.\",\n      \"method\": \"RNA immunoprecipitation, 5' UTR reporter assays, siRNA/overexpression, tumor initiation assays in xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-IP, 5'UTR reporter, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"25982283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IMP3 directly interacts with ULBP2 mRNA, leading to its destabilization and reduced ULBP2 surface expression in human cell lines, thereby impairing NK cell recognition. IMP3 also indirectly targets MICB through a mechanistically distinct pathway.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assays, NK cell cytotoxicity assays, flow cytometry for surface expression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP, mRNA stability, functional NK killing assay, multiple orthogonal methods\",\n      \"pmids\": [\"26982091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IMP3 and its partners ILF3/NF90 and PTBP1 bind to the 3' UTRs of cyclin D1 and D3 mRNAs and protect them from translational repression induced by AGO2/GW182-dependent miRNA pathway; upon IMP3 knockdown, cyclin mRNAs remain polysome-associated but are not translated, indicating regulation at the translational level.\",\n      \"method\": \"siRNA knockdown, polysome fractionation, 3' UTR binding assays, co-immunoprecipitation\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — polysome fractionation and co-IP in single lab, mechanistic follow-up of prior work\",\n      \"pmids\": [\"27840950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IMP3 forms circRNA-protein complexes (circRNPs) with a defined subset of circular RNAs in mammalian cells; glycerol gradient centrifugation revealed circRNPs of distinct sizes, and RNA-seq of IMP3-co-immunoprecipitated RNA identified specific IMP3-associated circRNAs. No evidence was found for efficient translation of these abundant circRNAs.\",\n      \"method\": \"Glycerol gradient centrifugation, co-immunoprecipitation of RNA, polysome gradient fractionation, RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (gradient sedimentation, co-IP, RNA-seq) in single study; negative result on translation is informative\",\n      \"pmids\": [\"27510448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IMP3 promotes glioma cell migration by directly binding p65 (RELA) mRNA 3' UTR and enhancing its translation (polysome association increased without change in transcript level); exogenous p65 from a 3'UTR-less construct rescued migration in IMP3-silenced cells. A positive feedback loop exists between IMP3 and NF-κB/p65, as IMP3 is transcriptionally activated by NF-κB.\",\n      \"method\": \"RNA immunoprecipitation-PCR, UV crosslinking with in vitro transcribed RNA, 3'UTR luciferase reporter (wild-type vs. mutant), polysome profiling, migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — UV crosslinking reconstitution, mutant UTR reporter, polysome profiling, and functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"28465487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IMP2 and IMP3 cooperate to promote TNBC metastasis by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT/CNOT1 complex, suppressing PR expression and thereby downregulating miR-200a; this forms a double-negative feedback loop.\",\n      \"method\": \"siRNA knockdown/overexpression, co-immunoprecipitation with CNOT1, mRNA stability assays, migration/invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with CNOT1, mRNA stability, functional assays in single lab\",\n      \"pmids\": [\"29217458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of IMP3 RRM12 reveals that both RRM domains adopt canonical RRM topology; only RRM1 contacts RNA and recognizes a dinucleotide sequence; the spatial orientation of RRM1 relative to RRM2 is unique compared to other tandem RRM structures.\",\n      \"method\": \"X-ray crystallography, biochemical RNA binding characterization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical validation in single rigorous study\",\n      \"pmids\": [\"30135093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IMP3 stabilizes WNT5B mRNA indirectly by repressing miR-145-5p (which targets WNT5B), leading to TAZ activation via alternative WNT signaling. IMP3 also facilitates SLUG transcription (required for TAZ nuclear localization) through a WNT5B-dependent mechanism, integrating Hippo and alternative WNT signaling pathways.\",\n      \"method\": \"mRNA stability assays, miRNA manipulation, siRNA/overexpression, reporter assays, breast cancer stem cell functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability, miRNA manipulation, multiple pathway readouts in single lab\",\n      \"pmids\": [\"29847788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IMP3 uses a combinatorial RNA recognition code involving all six RNA-binding domains (four KH and two RRM) to recognize a cluster of up to five distinct CA-rich and GGC-core RNA elements appropriately spaced across a >100 nucleotide target region; single-domain SELEX-seq, iCLIP, structural biology, and functional validation together define the RNA-binding specificity and RNP topology.\",\n      \"method\": \"Single-domain SELEX-seq, iCLIP, motif-spacing analysis, structural biology, functional reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-level SELEX, structural biology, in vivo iCLIP, functional validation; multiple orthogonal methods, highly systematic\",\n      \"pmids\": [\"31118463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-18 signaling induces shuttling of IMP3 and HuR from nucleus to cytoplasm and facilitates their interaction; the IMP3-HuR complex then binds the 3' UTR of COX-2 mRNA to stabilize it, contributing to chemoresistance in AML cells. JNK and/or ERK1/2 regulate HuR nucleocytoplasmic shuttling in this pathway.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, subcellular fractionation, mRNA stability assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP, co-IP, fractionation, single lab with multiple methods\",\n      \"pmids\": [\"26342105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RELB interacts with IMP3 and LIN28A in human pluripotent stem cells; these interactions control mRNA levels and protein expression of IGF2 and key cell-cycle genes; after stress, IMP3, LIN28, and RELB co-localize in stress granules.\",\n      \"method\": \"Co-immunoprecipitation, stress granule co-localization (immunofluorescence), quantitative PCR and western blot\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and localization data, single lab, limited functional follow-up on IMP3 specifically\",\n      \"pmids\": [\"25794352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IMP3 directly binds the 3' UTR of HK2 mRNA (hexokinase 2) to stabilize it; circCDKN2B-AS1 acts as a sponge for IMP3 protein, sequestering it and thereby modulating how much IMP3 is available to bind HK2 mRNA 3' UTR. Mutant circCDKN2B-AS1 lacking the IMP3 binding site lacks this effect.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, actinomycin-D mRNA stability assay, binding-site mutagenesis, western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down, RIP, mRNA stability, mutagenesis confirming binding site; single lab\",\n      \"pmids\": [\"33308298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IMP3 promotes prostate cancer progression by upregulating SMURF1 expression, which in turn facilitates PTEN ubiquitination and degradation, activating the PI3K/AKT/mTOR signaling pathway; SMURF1 knockdown rescues the proliferative and survival phenotypes induced by IMP3 overexpression.\",\n      \"method\": \"Immunoprecipitation/ubiquitination assay, siRNA/overexpression, western blot for PI3K/AKT/mTOR pathway components, in vivo tumor formation\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-ubiquitination, pathway epistasis by SMURF1 rescue, in vivo validation; single lab\",\n      \"pmids\": [\"32938489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IMP3 directly binds the 3' UTR of MEKK1 mRNA to stabilize it, promoting MEKK1 expression and sequentially activating MEK1/ERK signaling in colorectal cancer; IMP3 conditional knockout mice show decreased MEKK1 expression and reduced colorectal tumors in an AOM/DSS model.\",\n      \"method\": \"RNA immunoprecipitation, luciferase 3'UTR reporter assay, RNA-sequencing, conditional IMP3 knockout mouse, western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-IP, 3'UTR reporter, in vivo knockout mouse model, RNA-seq, multiple orthogonal methods\",\n      \"pmids\": [\"34154626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast/zebrafish model: Imp3 (as part of the Mpp10-Imp3-Imp4 complex) unfolds both the box A/A' stem in U3 snoRNA and helix 1 (H1) in the 18S region of pre-rRNA to promote U3-18S duplex formation required for small subunit processome cleavages at A0 and A1 sites; Imp3 binding alone provides sufficient energy for this unfolding, while Imp4 destabilizes the duplex to aid U3 release.\",\n      \"method\": \"Chemical modification probing, ribonuclease accessibility assay, in vitro reconstitution of U3-18S hybridization\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with chemical probing, mechanistic differentiation of Imp3 vs Imp4 roles; rigorous biochemical study\",\n      \"pmids\": [\"23980203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In zebrafish model: Sas10 determines the nucleolar localization of the Mpp10-Imp3-Imp4 complex; Sas10 protects Mpp10 from Capn3-mediated cleavage by masking the Capn3-recognition site, while Def interacts with Sas10 to form the Def-Sas10-Mpp10 complex that facilitates Capn3-mediated Mpp10 cleavage. Mpp10, but not Sas10, is a target of the Def-Capn3 degradation pathway.\",\n      \"method\": \"Zebrafish genetics, co-immunoprecipitation, nucleolar localization studies, protein stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, localization experiments, genetic model in zebrafish; single lab\",\n      \"pmids\": [\"30773582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IMP3 binds SLUG (SNAI2) mRNA directly (confirmed by ribo-immunoprecipitation qPCR) and regulates SLUG expression; IMP3 overexpression induces EMT markers (reduced E-cadherin, increased Slug and vimentin); knockdown of SLUG in IMP3-overexpressing cells reverses migration and invasion, and SLUG overexpression rescues invasion in IMP3-depleted cells, establishing SLUG as a functional downstream target of IMP3 in EMT.\",\n      \"method\": \"RNA immunoprecipitation-qPCR, siRNA knockdown/overexpression, Transwell migration/invasion assays, western blot for EMT markers\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP, epistasis rescue experiment, functional migration assay; single lab\",\n      \"pmids\": [\"25031719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IMP3 knockdown in pancreatic ductal adenocarcinoma cells significantly decreased cell motility, invasion, and extracellular matrix adhesion; IMP3-depleted cells showed reduced CD44 protein levels, decreased KIF11 mRNA, and reduced downstream RhoA signaling, indicating IMP3 modulates cytoskeletal organization via RhoA pathway.\",\n      \"method\": \"siRNA knockdown, Transwell migration/invasion assay, matrix adhesion assay, western blot for RhoA pathway\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional knockdown assays with pathway readout, replicated across multiple PDAC cell lines\",\n      \"pmids\": [\"25886367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IMP3 overexpression activates the NF-κB pathway in renal cell carcinoma cells, and pharmacological inhibition of NF-κB abrogates IMP3-promoted cell migration, placing IMP3 upstream of NF-κB in promoting RCC cell migration.\",\n      \"method\": \"Stable IMP3 overexpression, siRNA knockdown, RNA-seq, Transwell migration assay, NF-κB inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis via inhibitor, RNA-seq for global targets, functional migration assay; single lab\",\n      \"pmids\": [\"25919292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IMP3 knockdown in HeLa cervical cancer cells significantly reduced cell migration without altering cell proliferation, demonstrating a specific role of IMP3 in cell motility regulation.\",\n      \"method\": \"siRNA knockdown, scratch/wound-healing migration assay, proliferation assay\",\n      \"journal\": \"The American journal of surgical pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay, single cell line, no mechanistic pathway identified\",\n      \"pmids\": [\"21997684\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IMP3 (IGF2BP3) is a multidomain RNA-binding protein (two RRM and four KH domains) that uses a combinatorial recognition code—involving all six RNA-binding domains contacting clustered CA-rich and GGC-core motifs across >100 nucleotides—to bind and regulate specific target mRNAs at multiple levels: it acts as a translational activator (IGF-II, p65/RELA mRNAs via 5' UTR or polysome recruitment), stabilizes target mRNAs by sequestering them in cytoplasmic RNP granules that exclude the miRNA/AGO2 machinery (protecting HMGA2, LIN28B, and other let-7 targets from miRNA-directed decay), destabilizes select mRNAs (ULBP2, PR), and in the nucleus (where its localization depends on HNRNPM) regulates translation of cyclin D1, D3, and G1 mRNAs while protecting them from AGO2/GW182-mediated repression; through these mechanisms IMP3 promotes cell proliferation (via IGF-II and cyclin D1/D3), migration and invasion (via SLUG/EMT, RhoA, NF-κB, and p65), cancer stem cell self-renewal (via SLUG-SOX2 axis and TAZ/WNT5B), chemoresistance (via BCRP/ABCG2 and COX-2 mRNA stabilization), and tumor immune evasion (via ULBP2 mRNA destabilization reducing NK cell recognition), with upstream regulation by EGFR/MAPK signaling (inducing IMP3) and ERβ (repressing IMP3 indirectly via EGFR suppression); in ribosome biogenesis, Imp3 unfolds conserved stem structures in both U3 snoRNA and pre-rRNA 18S helix 1 to promote U3-18S duplex formation essential for small subunit processome cleavage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IMP3 (IGF2BP3) is a multidomain RNA-binding protein that post-transcriptionally controls the fate of specific target mRNAs to drive cell proliferation, migration, and tumor-associated programs [#0, #4, #6]. It engages targets through a combinatorial recognition code in which all six RNA-binding domains (four KH and two RRM) contact clustered CA-rich and GGC-core elements spaced across a >100-nucleotide region [#14]; structurally, only RRM1 of the tandem RRM12 module contacts RNA in a uniquely oriented arrangement [#12]. Mechanistically IMP3 operates at multiple levels: it acts as a translational activator, enhancing translation of IGF-II via its 5' UTR and of p65/RELA mRNA via increased polysome association [#0, #1, #10]; it stabilizes target mRNAs by sequestering them in cytoplasmic RNP granules depleted of the Ago/miRNA machinery, protecting let-7 targets such as HMGA2 and LIN28B from miRNA-directed decay [#5]; and it destabilizes select transcripts, including ULBP2 to impair NK-cell recognition and PR mRNA via recruitment of the CCR4-NOT/CNOT1 deadenylase complex [#7, #11]. In the nucleus, where its localization depends on the partner HNRNPM, IMP3 binds and is required for expression of cyclin D1, D3, and G1 mRNAs, protecting cyclin D mRNAs from AGO2/GW182-mediated translational repression together with ILF3/NF90 and PTBP1 [#4, #8]. Through these activities IMP3 promotes cancer stem-cell self-renewal via a SLUG/SNAI2-SOX2 axis and TAZ/WNT5B signaling [#6, #13, #22], chemoresistance via BCRP/ABCG2 and COX-2 mRNA stabilization [#3, #15], and migration/invasion via NF-\\u03baB, RhoA, and MEKK1/ERK signaling [#19, #23, #24], with upstream induction by EGFR/MAPK signaling and repression by ER\\u03b2 [#2]. Separately, in ribosome biogenesis IMP3 (as part of the Mpp10-Imp3-Imp4 complex) unfolds conserved stem structures in U3 snoRNA and pre-rRNA 18S helix 1 to promote U3-18S duplex formation required for small-subunit processome cleavage [#20, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established IMP3 as a sequence-specific translational activator rather than a transcriptional regulator, defining its core post-transcriptional mode of action on IGF-II mRNA.\",\n      \"evidence\": \"mRNP immunoprecipitation, siRNA knockdown, and chimeric leader-3/luciferase reporter in K562 cells\",\n      \"pmids\": [\"15753088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the RNA element or domains required for binding\", \"Limited to IGF-II among possible targets\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected IMP3-driven IGF-II translation to a physiological survival outcome, showing IMP3 promotes survival after ionizing radiation through 5' UTR-dependent IGF-II translation.\",\n      \"evidence\": \"5' UTR reporter constructs, siRNA knockdown, and recombinant IGF-II rescue in an IR-apoptosis model\",\n      \"pmids\": [\"21757716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IMP3 enhances 5' UTR translation not resolved\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined upstream control of IMP3, showing it is induced by EGFR/MAPK signaling and repressed by ER\\u03b2, embedding IMP3 in oncogenic signaling networks.\",\n      \"evidence\": \"Promoter reporter assays, RNA-IP, siRNA/overexpression, and migration/invasion assays\",\n      \"pmids\": [\"22266872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription factor binding to the IMP3 promoter not fully mapped\", \"CD164/MMP9 regulation mechanism not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended IMP3 targets to drug-resistance and cell-cycle machinery: it binds BCRP/ABCG2 mRNA to confer chemoresistance and is nuclear-enriched where it is required for cyclin D1/D3/G1 expression and G1 progression.\",\n      \"evidence\": \"RNA-IP, drug sensitivity assays, subcellular fractionation, and cell cycle analysis across multiple cancer lines; nuclear localization shown to depend on HNRNPM\",\n      \"pmids\": [\"23539627\", \"23812426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HNRNPM directs IMP3 nuclear import mechanistically unresolved\", \"Whether cyclin regulation is at stability or translation not distinguished here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a stabilization mechanism distinct from translational activation: IMP3 granules act as 'safe houses' that exclude the miRNA/Ago machinery to protect let-7 target mRNAs from decay.\",\n      \"evidence\": \"Transcriptome analysis, cytoplasmic granule fractionation, antagomiR experiments, and HMGA2 3' UTR deletion constructs; plus RNA-IP/EMT rescue defining SLUG as a downstream target\",\n      \"pmids\": [\"24703842\", \"25031719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What nucleates IMP3 granule assembly is unknown\", \"How granules physically exclude Ago not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked IMP3 to stem-cell self-renewal and stress responses, defining a SLUG-SOX2 axis for breast cancer stem cells and stress-granule co-localization with LIN28/RELB partners.\",\n      \"evidence\": \"RNA-IP, 5' UTR reporters, xenograft tumor-initiation assays; co-IP and stress-granule immunofluorescence; NF-\\u03baB inhibition and migration assays in RCC; IL-18-induced IMP3-HuR/COX-2 stabilization in AML\",\n      \"pmids\": [\"25982283\", \"25794352\", \"25919292\", \"26342105\", \"25886367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several mechanisms rest on single-lab co-IP or inhibitor epistasis\", \"Direct versus indirect target distinctions not always established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Diversified the regulatory repertoire to include mRNA destabilization and partner-assisted control: IMP3 destabilizes ULBP2 to evade NK cells, protects cyclin D mRNAs with ILF3/PTBP1, and assembles defined circRNP complexes.\",\n      \"evidence\": \"RNA-IP, mRNA stability and NK cytotoxicity assays; polysome fractionation and co-IP; glycerol-gradient/RNA-seq circRNP characterization\",\n      \"pmids\": [\"26982091\", \"27840950\", \"27510448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of stabilize-versus-destabilize outcome unknown\", \"Functional role of IMP3-bound circRNAs unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed IMP3 drives migration through reinforcing feedback loops: it enhances p65/RELA translation in a positive loop with NF-\\u03baB, and cooperates with IMP2 to destabilize PR mRNA via CCR4-NOT.\",\n      \"evidence\": \"UV crosslinking, mutant 3' UTR reporters, polysome profiling, and rescue for p65; co-IP with CNOT1 and stability assays for PR\",\n      \"pmids\": [\"28465487\", \"29217458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CNOT1 recruitment mechanism by IMP3 not structurally defined\", \"p65 loop validated mainly in glioma context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the molecular and structural basis for IMP3 specificity, defining a six-domain combinatorial recognition code and a unique tandem-RRM architecture.\",\n      \"evidence\": \"Single-domain SELEX-seq, iCLIP, motif-spacing analysis, and crystallography of RRM12\",\n      \"pmids\": [\"31118463\", \"30135093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length six-domain RNP structure on a native target not solved\", \"How recognition code dictates stabilize-vs-destabilize fate not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded IMP3 targets into metabolic and signaling regulators and showed its activity is itself tunable by circRNA sponging.\",\n      \"evidence\": \"RNA pull-down, RIP, actinomycin-D stability assays, and binding-site mutagenesis for HK2/circCDKN2B-AS1; IP-ubiquitination and SMURF1 rescue for the PTEN-PI3K/AKT axis\",\n      \"pmids\": [\"33308298\", \"32938489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab validation of each axis\", \"Generality of circRNA sponging of IMP3 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided in vivo genetic confirmation of IMP3-driven tumorigenesis through MEKK1/ERK signaling in colorectal cancer.\",\n      \"evidence\": \"RNA-IP, 3' UTR luciferase reporter, RNA-seq, and conditional IMP3 knockout in an AOM/DSS mouse model\",\n      \"pmids\": [\"34154626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue specificity of MEKK1 stabilization not explored\", \"Relationship to other IMP3 migration pathways not integrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a mechanistically separate, conserved role for Imp3 in ribosome biogenesis as an RNA-structure chaperone unfolding U3 snoRNA and pre-rRNA stems to enable processome cleavage.\",\n      \"evidence\": \"Chemical modification probing, ribonuclease accessibility, and in vitro reconstitution of U3-18S hybridization in yeast/zebrafish; zebrafish genetics defining Sas10/Def-dependent nucleolar localization and Mpp10 stability\",\n      \"pmids\": [\"23980203\", \"30773582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this processome role exists in human cells alongside mRNA functions not addressed in this corpus\", \"How the same protein partitions between nucleolar and cytoplasmic mRNA roles unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular features of a bound transcript determine whether IMP3 stabilizes, destabilizes, or translationally activates it, and how IMP3 partitions between its mRNA-regulatory and ribosome-biogenesis functions.\",\n      \"evidence\": \"No single discovery in the corpus reconciles the divergent regulatory outcomes or the dual nucleolar/cytoplasmic roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying rule linking RNA recognition code to regulatory outcome\", \"No structure of full-length IMP3 on a native target\", \"Crosstalk between processome and mRNA roles uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 5, 7, 12, 14]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 8, 10]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 7, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 19, 24]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 18, 19]}\n    ],\n    \"complexes\": [\n      \"Mpp10-Imp3-Imp4 complex\",\n      \"IMP3-HuR complex\"\n    ],\n    \"partners\": [\n      \"HNRNPM\",\n      \"ILF3\",\n      \"PTBP1\",\n      \"CNOT1\",\n      \"HuR\",\n      \"LIN28A\",\n      \"RELB\",\n      \"IMP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"IMP3","tier":"IDENTITY","verdict":"Identity concern","subtype":"paralog","uniprot_band":"rich","rules_fired":"R3","issue":"R3: opener equates IMP3 to different HGNC gene IGF2BP3"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}