{"gene":"EIF3I","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1998,"finding":"TRIP-1 (EIF3I) associates with the TGF-β type II receptor and is phosphorylated by it. TRIP-1 overexpression represses TGF-β-induced transcription from the PAI-1 promoter and inhibits PAI-1 expression induced by Smads and activated TGF-β type I receptors, acting through both receptor-dependent and receptor-independent mechanisms. Deletion mutational analysis identified two distinct non-WD40 regions required for this inhibitory activity.","method":"Co-IP/association assay, reporter gene assay (PAI-1 promoter), deletion mutagenesis, transfection overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor association established, functional reporter assays with deletion mapping, single lab but multiple orthogonal methods","pmids":["9813058"],"is_preprint":false},{"year":2010,"finding":"A single-point mutation in WD40 repeat 6 of yeast eIF3i/Tif34 (Q258R) causes severe growth defects, decreases the rate of translation initiation in vivo, diminishes GCN4 induction, and impairs the rate of scanning of post-termination 40S ribosomes moving downstream from uORF1, without affecting eIF3 complex integrity or 43S PIC formation. This implicates eIF3i in stimulation of linear scanning.","method":"Genetic point mutation, in vivo translation assays, GCN4 reporter assay, polysome analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (growth assays, translation rate measurement, GCN4 reporter, polysome profiling), rigorous genetic dissection in yeast ortholog","pmids":["20679478"],"is_preprint":false},{"year":2006,"finding":"Overexpression of eIF3i in human cells causes cell size increase, proliferation enhancement, cell-cycle progression, and anchorage-independent growth in an mTOR-dependent manner; rapamycin (mTOR inhibitor) reduces serine phosphorylation of eIF3i and abolishes anchorage-independent growth, indicating mTOR phosphorylates eIF3i on serine and that this is required for its oncogenic activity.","method":"Overexpression in cell lines, rapamycin treatment, phosphorylation assay, anchorage-independent growth assay","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional phenotype with pharmacological intervention identifying mTOR as upstream kinase, single lab, two orthogonal methods","pmids":["16929481"],"is_preprint":false},{"year":2013,"finding":"eIF3I physically interacts with Akt1 in HCC cell lines and tissues; the C-terminal domain of eIF3I interacts with the Akt1 kinase domain. This interaction prevents PP2A-mediated dephosphorylation of Akt1, resulting in constitutively active Akt1 oncogenic signaling. Dominant negative Akt1 or antisense eIF3I suppresses eIF3I-mediated tumorigenesis.","method":"Co-IP in cell lines and tissues, oncogenic domain mapping, dominant-negative mutant rescue, in vitro and in vivo tumorigenesis assays, PP2A dephosphorylation assay","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in multiple contexts, domain mapping, functional rescue with DN mutant, mechanism (PP2A exclusion) established with multiple orthogonal approaches","pmids":["23460382"],"is_preprint":false},{"year":2013,"finding":"eIF3i overexpression in intestinal epithelial cells directly upregulates COX-2 protein synthesis at the translational level and activates the β-catenin/TCF4 signaling pathway, driving colon oncogenesis.","method":"Ectopic overexpression, polysome profiling/translational assay, reporter assays for β-catenin/TCF4, in vitro oncogenesis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — translational upregulation of COX-2 and β-catenin pathway activation demonstrated with multiple assays, single lab","pmids":["24056964"],"is_preprint":false},{"year":2014,"finding":"eIF3i is required for VEGFA protein expression under hypoxia. HIF1A binds the eIF3i promoter and activates eIF3i transcription under hypoxia. eIF3i knockdown specifically reduces translational efficiency of VEGFA mRNA without causing general translation repression, establishing eIF3i as a selective translational regulator of VEGFA downstream of HIF1A.","method":"ChIP for HIF1A at eIF3i promoter, siRNA knockdown, polysome profiling, zebrafish eIF3i mutant angiogenesis assay, tumor xenograft angiogenesis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, polysome profiling, genetic mutant in zebrafish, in vivo tumor model), mechanistic chain from HIF1A→eIF3i→VEGFA translation established","pmids":["25147179"],"is_preprint":false},{"year":2014,"finding":"In primary human lung fibroblasts, knockdown of TRIP-1 (EIF3I) drives fibroblast-to-myofibroblast transdifferentiation (α-SMA induction, collagen contraction, apoptosis resistance) via enhanced AKT phosphorylation, independent of Smad3 signaling. A constitutively active AKT construct mimics TRIP-1 knockdown effects, and AKT inhibition prevents α-SMA induction in TRIP-1 knockdown cells.","method":"siRNA knockdown, plasmid overexpression, AKT inhibitor treatment, constitutively active AKT construct, α-SMA expression assay, collagen contraction assay, Smad3 knockdown epistasis","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments with multiple genetic manipulations identify AKT as downstream effector, single lab","pmids":["24528651"],"is_preprint":false},{"year":2015,"finding":"CLU (clusterin) activates Akt signaling by complexing with EIF3I; this complex promotes MMP13 expression and HCC metastasis. CLU knockdown via OGX-011 suppresses HCC metastasis through inhibiting EIF3I/Akt/MMP13 signaling.","method":"Co-IP (CLU-EIF3I complex), in vitro and in vivo invasion/metastasis assays, CLU knockdown, pathway inhibition","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP establishing CLU-EIF3I complex with functional in vivo validation, single lab","pmids":["25609201"],"is_preprint":false},{"year":2017,"finding":"eIF3i knockdown in endothelial cells reduces VEGFR2 and ERK protein expression (selective translational downregulation), restraining endothelial cell proliferation and migration. In zebrafish, eIF3i mutant endothelial cells fail to respond to tumor-derived induction signals, establishing eIF3i as a selective translational regulator of VEGFR/ERK signaling in endothelial cells.","method":"siRNA knockdown, zebrafish eIF3i mutant, cell proliferation/migration assays, Western blot for VEGFR2/ERK, gene therapy shRNA model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant in zebrafish plus knockdown in cell lines with protein-level readouts, single lab","pmids":["28193911"],"is_preprint":false},{"year":2017,"finding":"EIF3I physically interacts with VSV matrix protein (M protein) as identified by yeast two-hybrid, validated by GST pull-down and co-localization. Mutagenesis of M (aa 122–181) impairs but does not abolish the interaction. EIF3I knockdown modulates VSV replication/transcription in a time-dependent manner and inhibits ISG expression regulated by phospho-Akt1.","method":"Yeast two-hybrid, GST pull-down, laser confocal co-localization, mutagenesis of M protein, siRNA knockdown, viral replication assay","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction validated by two orthogonal methods (GST pull-down + co-localization) with mutagenesis, single lab","pmids":["29173589"],"is_preprint":false},{"year":2018,"finding":"TRIP-1 (EIF3I) is localized in the extracellular matrix of bone and dentin, and promotes nucleation of calcium phosphate polymorphs including hydroxyapatite crystals. Recombinant TRIP-1 at varying concentrations orchestrates hydroxyapatite formation on demineralized dentin collagen under physiological conditions.","method":"In vivo implantation assay, recombinant protein nucleation experiments, TEM analysis of mineral deposits, overexpression/knockdown ECM analysis","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution of nucleation with recombinant protein plus in vivo implantation, single lab","pmids":["29745814"],"is_preprint":false},{"year":2021,"finding":"PD-L1 directly binds EIF3I and promotes cutaneous wound healing by downregulating IRS4; the EIF3I–PD-L1–IRS4 axis was identified by immunoprecipitation combined with mass spectrometry and validated by co-immunoprecipitation assays with in vivo and in vitro functional testing.","method":"Co-IP with mass spectrometry, co-immunoprecipitation validation, in vivo and in vitro functional assays for wound healing","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction identified by IP-MS and validated by Co-IP with functional in vivo testing, single lab","pmids":["34293353"],"is_preprint":false},{"year":2022,"finding":"Lenalidomide (via the E3 ligase adapter CRBN) recruits eIF3i but does not degrade it; instead, it sequesters eIF3i from the eIF3 complex. The binding interface on eIF3i was identified by a covalent lenalidomide probe and mass spectrometry. This sequestration drives effects on angiogenic markers, Akt1 phosphorylation, and antiangiogenesis phenotypes.","method":"Covalent chemical probe + mass spectrometry mapping of binding interface, chemical proteomics, Co-IP for eIF3 complex disruption, cell-based angiogenesis and Akt1 phosphorylation assays","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — covalent probe with mass spectrometry for interface mapping (Tier 1 chemical biology), functional validation in cells, single lab but multiple orthogonal methods","pmids":["36325969"],"is_preprint":false},{"year":2023,"finding":"eIF3i directly promotes PHGDH translation in colorectal cancer cells. METTL3-mediated m6A modification on PHGDH mRNA promotes its binding to eIF3i, leading to higher translational rate of PHGDH. PHGDH knockdown partially attenuates the excessive growth induced by eIF3i overexpression.","method":"Ribosome profiling, proteomics, m6A modification analysis, RIP assay for eIF3i-PHGDH mRNA binding, siRNA knockdown epistasis, in vivo tumor growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ribosome profiling plus RIP plus m6A analysis plus epistasis knockdown, multiple orthogonal methods in single study","pmids":["37611825"],"is_preprint":false},{"year":2024,"finding":"lnc-TSPAN12 acts as a scaffold that enhances the SENP1-EIF3I interaction, inhibiting SUMOylation of EIF3I and preventing its ubiquitin-mediated degradation, thereby stabilizing EIF3I protein levels and activating Wnt/β-catenin signaling to promote EMT and HCC metastasis.","method":"Co-IP (EIF3I-SENP1 interaction), RNA pull-down, SUMOylation assay, ubiquitination assay, lncRNA knockdown/overexpression, in vivo metastasis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation/ubiquitination assays with Co-IP validation and in vivo functional testing, single lab","pmids":["38374407"],"is_preprint":false},{"year":2025,"finding":"eIF3i directly binds NELFCD mRNA and promotes its translation, independent of transcription. eIF3i-driven NELFCD upregulation facilitates EMT and invadopodia formation, promoting CRC metastasis. NELFCD knockdown abolishes the pro-metastatic effects of eIF3i overexpression.","method":"Polysome profiling, RNA-binding assays (RIP and RNA pull-down), in vitro migration/invasion assays, in vivo mouse metastatic models, epistasis knockdown","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA binding validated by RIP and RNA pull-down, polysome profiling, epistasis knockdown, single lab","pmids":["41315067"],"is_preprint":false},{"year":2025,"finding":"Loss-of-function mutations in eIF3i (yeast ortholog) reduce translation of GFP reporters with both short and long unstructured 5′ UTRs to a similar extent as mutations in other scanning factors (eIF4A, Ded1, eIF4G, eIF4B, eIF3g), and severely diminish translation of reporters with structured 5′ UTRs. This is consistent with eIF3i facilitating mRNA scanning and secondary structure unwinding rather than being the rate-limiting helicase-driven translocase.","method":"GFP reporter assay in S. cerevisiae, loss-of-function mutations in eIF3i and comparison with other initiation factor mutants","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single reporter system, indirect inference about mechanism from comparative mutant analysis","pmids":["bio_10.1101_2024.12.30.630811"],"is_preprint":true}],"current_model":"EIF3I (TRIP-1/eIF3-p36) is a WD40-repeat subunit of the eIF3 complex that functions both as a general translation initiation factor (stimulating 43S PIC scanning and mRNA translation) and as a selective translational regulator—directly binding specific mRNAs (VEGFA, PHGDH, NELFCD, COX-2) to enhance their translation; it also acts as a signaling hub that interacts with the TGF-β type II receptor (being phosphorylated by it to modulate Smad signaling), forms a complex with Akt1 to block PP2A-mediated dephosphorylation and sustain constitutive Akt1 activity, undergoes mTOR-mediated serine phosphorylation, and can be sequestered from the eIF3 complex by lenalidomide-bound CRBN, collectively explaining its roles in cell growth, angiogenesis, fibrosis, and oncogenesis."},"narrative":{"mechanistic_narrative":"EIF3I (TRIP-1/eIF3-p36) is a WD40-repeat subunit of the eIF3 translation-initiation complex that operates both as a general initiation factor and as a selective translational regulator coupling growth and survival signaling to protein synthesis [PMID:20679478, PMID:25147179]. Genetic dissection of the yeast ortholog establishes that eIF3i stimulates linear 43S scanning of post-termination 40S ribosomes without affecting eIF3 integrity or 43S PIC formation [PMID:20679478]. Beyond bulk initiation, eIF3i directly binds and selectively enhances translation of specific mRNAs—VEGFA under hypoxia downstream of HIF1A, PHGDH (whose binding is favored by METTL3-deposited m6A), and NELFCD—thereby promoting angiogenesis, metabolic rewiring, EMT, and metastasis [PMID:25147179, PMID:37611825, PMID:41315067]. EIF3I also serves as a signaling hub: it associates with the TGF-β type II receptor and is phosphorylated by it to repress Smad-driven PAI-1 transcription [PMID:9813058], and it binds the Akt1 kinase domain through its C-terminus to block PP2A-mediated dephosphorylation and sustain constitutive Akt1 activity that drives hepatocellular tumorigenesis and fibroblast-to-myofibroblast transdifferentiation [PMID:23460382, PMID:24528651]. Its oncogenic activity requires mTOR-dependent serine phosphorylation [PMID:16929481], and its protein level is controlled by a SUMOylation/ubiquitination axis that, when stabilized, activates Wnt/β-catenin signaling [PMID:38374407]. Pharmacologically, CRBN-bound lenalidomide sequesters eIF3i from the eIF3 complex without degrading it, producing antiangiogenic effects [PMID:36325969].","teleology":[{"year":1998,"claim":"Established the first signaling role for EIF3I beyond translation by showing it is a receptor-associated substrate that modulates TGF-β transcriptional output.","evidence":"Co-IP receptor association, PAI-1 promoter reporter assay, and deletion mutagenesis in transfected cells","pmids":["9813058"],"confidence":"Medium","gaps":["Physiological phosphorylation sites on EIF3I by TGF-βRII not mapped","Receptor-independent mechanism of Smad repression undefined","Relationship to its eIF3 role unaddressed"]},{"year":2006,"claim":"Connected EIF3I to growth control by identifying mTOR-dependent serine phosphorylation as a requirement for its proliferative and transforming activity.","evidence":"Overexpression with rapamycin treatment, phosphorylation and anchorage-independent growth assays in cell lines","pmids":["16929481"],"confidence":"Medium","gaps":["Specific serine residue(s) not identified","Direct versus indirect mTOR phosphorylation not resolved","Mechanistic link between phosphorylation and oncogenic output unclear"]},{"year":2010,"claim":"Pinpointed the molecular contribution of eIF3i within initiation, showing it stimulates linear 40S scanning rather than complex assembly or PIC formation.","evidence":"WD40-repeat point mutation (Q258R) with in vivo translation rate, GCN4 reporter, and polysome analyses in yeast","pmids":["20679478"],"confidence":"High","gaps":["Molecular basis of scanning stimulation by the WD40 domain unknown","Generality to human eIF3I not directly tested","No structural model of the scanning step"]},{"year":2013,"claim":"Defined a direct oncogenic mechanism in which EIF3I sustains Akt1 activity, and separately showed selective translational control of COX-2.","evidence":"Reciprocal Co-IP, C-terminal domain mapping, PP2A dephosphorylation assay, dominant-negative rescue, and tumorigenesis assays; polysome and β-catenin/TCF4 reporter assays","pmids":["23460382","24056964"],"confidence":"High","gaps":["Structural detail of the EIF3I–Akt1 interface absent","How EIF3I physically excludes PP2A unresolved","Mechanism of selective COX-2 mRNA translation not defined"]},{"year":2014,"claim":"Established EIF3I as a HIF1A-induced selective translational regulator of VEGFA and as an Akt-acting node in fibrosis, broadening its physiological reach.","evidence":"ChIP, siRNA knockdown, polysome profiling, zebrafish mutant angiogenesis and xenograft models; fibroblast transdifferentiation with AKT epistasis","pmids":["25147179","24528651"],"confidence":"High","gaps":["RNA features conferring VEGFA selectivity unidentified","Whether VEGFA binding is direct not fully resolved","Smad-independent route to AKT activation in fibroblasts mechanistically incomplete"]},{"year":2015,"claim":"Extended the EIF3I–Akt axis to metastasis by showing clusterin partners with EIF3I to drive MMP13 expression.","evidence":"Co-IP of CLU-EIF3I, invasion/metastasis assays, and CLU knockdown in HCC","pmids":["25609201"],"confidence":"Medium","gaps":["Direct versus indirect CLU–EIF3I binding not established","No reciprocal interaction mapping","Link between complex formation and MMP13 induction mechanistic gap"]},{"year":2017,"claim":"Showed EIF3I selectively controls translation of pro-angiogenic effectors (VEGFR2/ERK) in endothelial cells and identified a physical interaction with VSV M protein affecting viral replication.","evidence":"siRNA knockdown, zebrafish mutant, proliferation/migration assays, Western blot; yeast two-hybrid, GST pull-down, co-localization, viral replication assay","pmids":["28193911","29173589"],"confidence":"Medium","gaps":["Basis of VEGFR2/ERK mRNA selectivity unknown","Functional consequence of VSV M binding incompletely defined","Whether viral effect depends on the eIF3 complex unclear"]},{"year":2018,"claim":"Revealed a non-canonical extracellular function in which EIF3I/TRIP-1 nucleates hydroxyapatite in mineralized matrix.","evidence":"In vivo implantation, recombinant protein nucleation experiments, and TEM of mineral deposits","pmids":["29745814"],"confidence":"Medium","gaps":["Mechanism of secretion to the ECM unknown","Relationship to its intracellular eIF3 role unexplained","Domain mediating mineral nucleation unmapped"]},{"year":2021,"claim":"Identified a PD-L1–EIF3I–IRS4 axis linking EIF3I to wound healing.","evidence":"IP-MS discovery, Co-IP validation, and in vivo/in vitro wound-healing functional assays","pmids":["34293353"],"confidence":"Medium","gaps":["Direct binding interface not mapped","How EIF3I downregulates IRS4 mechanistically unclear","Translation-dependence of the effect untested"]},{"year":2022,"claim":"Demonstrated a druggable, non-degradative mechanism in which CRBN-bound lenalidomide sequesters eIF3i out of the eIF3 complex, with antiangiogenic consequences.","evidence":"Covalent lenalidomide probe with mass-spectrometry interface mapping, chemical proteomics, Co-IP for complex disruption, and cell-based assays","pmids":["36325969"],"confidence":"High","gaps":["Quantitative effect on global translation not defined","Selectivity of sequestration over other eIF3 subunits unaddressed","In vivo relevance of the antiangiogenic effect untested"]},{"year":2023,"claim":"Connected RNA modification to selective translation by showing METTL3-deposited m6A on PHGDH mRNA promotes its binding to eIF3i and enhanced translation.","evidence":"Ribosome profiling, proteomics, m6A analysis, RIP for eIF3i-PHGDH binding, and epistasis knockdown with in vivo tumor assays","pmids":["37611825"],"confidence":"High","gaps":["Whether eIF3i directly reads m6A marks not resolved","Structural basis of mRNA recognition unknown","Breadth of m6A-dependent target set undefined"]},{"year":2024,"claim":"Defined post-translational control of EIF3I abundance, showing a SENP1/lnc-TSPAN12 axis blocks its SUMOylation-dependent degradation to activate Wnt/β-catenin signaling.","evidence":"Co-IP, RNA pull-down, SUMOylation and ubiquitination assays, lncRNA manipulation, and in vivo metastasis assays","pmids":["38374407"],"confidence":"Medium","gaps":["SUMOylation site(s) on EIF3I not mapped","E3 ligase mediating ubiquitination unidentified","Link between EIF3I stabilization and Wnt activation mechanistically incomplete"]},{"year":2025,"claim":"Added NELFCD to the set of directly bound mRNAs selectively translated by eIF3i to drive EMT and invadopodia formation in colorectal cancer.","evidence":"Polysome profiling, RIP and RNA pull-down, migration/invasion assays, in vivo metastasis models, and epistasis knockdown","pmids":["41315067"],"confidence":"Medium","gaps":["Sequence/structural determinants of NELFCD mRNA selectivity unknown","Whether binding requires the full eIF3 complex untested","Generalizable rules for eIF3i target selection still lacking"]},{"year":null,"claim":"How eIF3i achieves selective recognition of specific mRNAs (VEGFA, PHGDH, NELFCD, COX-2) versus its general scanning role within eIF3 remains the central unresolved question.","evidence":"No single study reconciles target-selective binding with the WD40-domain scanning mechanism","pmids":[],"confidence":"Low","gaps":["No structure of human EIF3I bound to a target mRNA","Determinants distinguishing selective targets from bulk mRNAs undefined","Whether selective translation occurs within or outside the canonical eIF3 complex unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,13,15]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[1,5,13,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,5,13,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,13,14,15]}],"complexes":["eIF3 complex"],"partners":["AKT1","TGFBR2","CLU","CD274","SENP1","CRBN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13347","full_name":"Eukaryotic translation initiation factor 3 subunit I","aliases":["Eukaryotic translation initiation factor 3 subunit 2","TGF-beta receptor-interacting protein 1","TRIP-1","eIF-3-beta","eIF3 p36"],"length_aa":325,"mass_kda":36.5,"function":"Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13347/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3I","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000084623","cell_line_id":"CID001691","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3M","stoichiometry":10.0},{"gene":"RPS11","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":4.0},{"gene":"EIF3E","stoichiometry":4.0},{"gene":"EIF3L","stoichiometry":4.0},{"gene":"EIF3K","stoichiometry":4.0},{"gene":"RACK1","stoichiometry":4.0},{"gene":"RPL5","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001691","total_profiled":1310},"omim":[{"mim_id":"603911","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT I; EIF3I","url":"https://www.omim.org/entry/603911"},{"mim_id":"603910","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT J; EIF3J","url":"https://www.omim.org/entry/603910"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3I"},"hgnc":{"alias_symbol":["TRIP-1","eIF3-beta","eIF3-p36"],"prev_symbol":["EIF3S2"]},"alphafold":{"accession":"Q13347","domains":[{"cath_id":"2.130.10.10","chopping":"10-145","consensus_level":"medium","plddt":94.8328,"start":10,"end":145},{"cath_id":"2.130.10.10","chopping":"200-325","consensus_level":"medium","plddt":90.002,"start":200,"end":325}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13347","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13347-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13347-F1-predicted_aligned_error_v6.png","plddt_mean":91.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3I","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3I"},"sequence":{"accession":"Q13347","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13347.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13347/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13347"}},"corpus_meta":[{"pmid":"9813058","id":"PMC_9813058","title":"The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9813058","citation_count":101,"is_preprint":false},{"pmid":"20679478","id":"PMC_20679478","title":"The RNA recognition motif of eukaryotic translation initiation factor 3g (eIF3g) is required for resumption of scanning of posttermination ribosomes for reinitiation on GCN4 and together with eIF3i stimulates linear scanning.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20679478","citation_count":93,"is_preprint":false},{"pmid":"25609201","id":"PMC_25609201","title":"Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25609201","citation_count":56,"is_preprint":false},{"pmid":"16929481","id":"PMC_16929481","title":"Carcinoma-associated eIF3i overexpression facilitates mTOR-dependent growth transformation.","date":"2006","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/16929481","citation_count":45,"is_preprint":false},{"pmid":"23460382","id":"PMC_23460382","title":"Overexpressed-eIF3I interacted and activated oncogenic Akt1 is a theranostic target in human hepatocellular carcinoma.","date":"2013","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23460382","citation_count":44,"is_preprint":false},{"pmid":"24056964","id":"PMC_24056964","title":"EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and β-catenin activation.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24056964","citation_count":37,"is_preprint":false},{"pmid":"30680888","id":"PMC_30680888","title":"Metabolic reconstruction of the genome of candidate Desulfatiglans TRIP_1 and identification of key candidate enzymes for anaerobic phenanthrene degradation.","date":"2019","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30680888","citation_count":36,"is_preprint":false},{"pmid":"32061967","id":"PMC_32061967","title":"Engineered transient and stable overexpression of translation factors eIF3i and eIF3c in CHOK1 and HEK293 cells gives enhanced cell growth associated with increased c-Myc expression and increased recombinant protein synthesis.","date":"2020","source":"Metabolic engineering","url":"https://pubmed.ncbi.nlm.nih.gov/32061967","citation_count":26,"is_preprint":false},{"pmid":"25147179","id":"PMC_25147179","title":"The translation initiation factor eIF3i up-regulates vascular endothelial growth factor A, accelerates cell proliferation, and promotes angiogenesis in embryonic development and tumorigenesis.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25147179","citation_count":24,"is_preprint":false},{"pmid":"31765158","id":"PMC_31765158","title":"Cancer Targeted Gene Therapy for Inhibition of Melanoma Lung Metastasis with eIF3i shRNA Loaded Liposomes.","date":"2019","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/31765158","citation_count":22,"is_preprint":false},{"pmid":"21378021","id":"PMC_21378021","title":"TRIP-1 regulates TGF-β1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549.","date":"2011","source":"American journal of physiology. 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TRIP-1 overexpression represses TGF-β-induced transcription from the PAI-1 promoter and inhibits PAI-1 expression induced by Smads and activated TGF-β type I receptors, acting through both receptor-dependent and receptor-independent mechanisms. Deletion mutational analysis identified two distinct non-WD40 regions required for this inhibitory activity.\",\n      \"method\": \"Co-IP/association assay, reporter gene assay (PAI-1 promoter), deletion mutagenesis, transfection overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor association established, functional reporter assays with deletion mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9813058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A single-point mutation in WD40 repeat 6 of yeast eIF3i/Tif34 (Q258R) causes severe growth defects, decreases the rate of translation initiation in vivo, diminishes GCN4 induction, and impairs the rate of scanning of post-termination 40S ribosomes moving downstream from uORF1, without affecting eIF3 complex integrity or 43S PIC formation. This implicates eIF3i in stimulation of linear scanning.\",\n      \"method\": \"Genetic point mutation, in vivo translation assays, GCN4 reporter assay, polysome analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (growth assays, translation rate measurement, GCN4 reporter, polysome profiling), rigorous genetic dissection in yeast ortholog\",\n      \"pmids\": [\"20679478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of eIF3i in human cells causes cell size increase, proliferation enhancement, cell-cycle progression, and anchorage-independent growth in an mTOR-dependent manner; rapamycin (mTOR inhibitor) reduces serine phosphorylation of eIF3i and abolishes anchorage-independent growth, indicating mTOR phosphorylates eIF3i on serine and that this is required for its oncogenic activity.\",\n      \"method\": \"Overexpression in cell lines, rapamycin treatment, phosphorylation assay, anchorage-independent growth assay\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional phenotype with pharmacological intervention identifying mTOR as upstream kinase, single lab, two orthogonal methods\",\n      \"pmids\": [\"16929481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"eIF3I physically interacts with Akt1 in HCC cell lines and tissues; the C-terminal domain of eIF3I interacts with the Akt1 kinase domain. This interaction prevents PP2A-mediated dephosphorylation of Akt1, resulting in constitutively active Akt1 oncogenic signaling. Dominant negative Akt1 or antisense eIF3I suppresses eIF3I-mediated tumorigenesis.\",\n      \"method\": \"Co-IP in cell lines and tissues, oncogenic domain mapping, dominant-negative mutant rescue, in vitro and in vivo tumorigenesis assays, PP2A dephosphorylation assay\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in multiple contexts, domain mapping, functional rescue with DN mutant, mechanism (PP2A exclusion) established with multiple orthogonal approaches\",\n      \"pmids\": [\"23460382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"eIF3i overexpression in intestinal epithelial cells directly upregulates COX-2 protein synthesis at the translational level and activates the β-catenin/TCF4 signaling pathway, driving colon oncogenesis.\",\n      \"method\": \"Ectopic overexpression, polysome profiling/translational assay, reporter assays for β-catenin/TCF4, in vitro oncogenesis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — translational upregulation of COX-2 and β-catenin pathway activation demonstrated with multiple assays, single lab\",\n      \"pmids\": [\"24056964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"eIF3i is required for VEGFA protein expression under hypoxia. HIF1A binds the eIF3i promoter and activates eIF3i transcription under hypoxia. eIF3i knockdown specifically reduces translational efficiency of VEGFA mRNA without causing general translation repression, establishing eIF3i as a selective translational regulator of VEGFA downstream of HIF1A.\",\n      \"method\": \"ChIP for HIF1A at eIF3i promoter, siRNA knockdown, polysome profiling, zebrafish eIF3i mutant angiogenesis assay, tumor xenograft angiogenesis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, polysome profiling, genetic mutant in zebrafish, in vivo tumor model), mechanistic chain from HIF1A→eIF3i→VEGFA translation established\",\n      \"pmids\": [\"25147179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In primary human lung fibroblasts, knockdown of TRIP-1 (EIF3I) drives fibroblast-to-myofibroblast transdifferentiation (α-SMA induction, collagen contraction, apoptosis resistance) via enhanced AKT phosphorylation, independent of Smad3 signaling. A constitutively active AKT construct mimics TRIP-1 knockdown effects, and AKT inhibition prevents α-SMA induction in TRIP-1 knockdown cells.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, AKT inhibitor treatment, constitutively active AKT construct, α-SMA expression assay, collagen contraction assay, Smad3 knockdown epistasis\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments with multiple genetic manipulations identify AKT as downstream effector, single lab\",\n      \"pmids\": [\"24528651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CLU (clusterin) activates Akt signaling by complexing with EIF3I; this complex promotes MMP13 expression and HCC metastasis. CLU knockdown via OGX-011 suppresses HCC metastasis through inhibiting EIF3I/Akt/MMP13 signaling.\",\n      \"method\": \"Co-IP (CLU-EIF3I complex), in vitro and in vivo invasion/metastasis assays, CLU knockdown, pathway inhibition\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP establishing CLU-EIF3I complex with functional in vivo validation, single lab\",\n      \"pmids\": [\"25609201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"eIF3i knockdown in endothelial cells reduces VEGFR2 and ERK protein expression (selective translational downregulation), restraining endothelial cell proliferation and migration. In zebrafish, eIF3i mutant endothelial cells fail to respond to tumor-derived induction signals, establishing eIF3i as a selective translational regulator of VEGFR/ERK signaling in endothelial cells.\",\n      \"method\": \"siRNA knockdown, zebrafish eIF3i mutant, cell proliferation/migration assays, Western blot for VEGFR2/ERK, gene therapy shRNA model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant in zebrafish plus knockdown in cell lines with protein-level readouts, single lab\",\n      \"pmids\": [\"28193911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EIF3I physically interacts with VSV matrix protein (M protein) as identified by yeast two-hybrid, validated by GST pull-down and co-localization. Mutagenesis of M (aa 122–181) impairs but does not abolish the interaction. EIF3I knockdown modulates VSV replication/transcription in a time-dependent manner and inhibits ISG expression regulated by phospho-Akt1.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, laser confocal co-localization, mutagenesis of M protein, siRNA knockdown, viral replication assay\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction validated by two orthogonal methods (GST pull-down + co-localization) with mutagenesis, single lab\",\n      \"pmids\": [\"29173589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIP-1 (EIF3I) is localized in the extracellular matrix of bone and dentin, and promotes nucleation of calcium phosphate polymorphs including hydroxyapatite crystals. Recombinant TRIP-1 at varying concentrations orchestrates hydroxyapatite formation on demineralized dentin collagen under physiological conditions.\",\n      \"method\": \"In vivo implantation assay, recombinant protein nucleation experiments, TEM analysis of mineral deposits, overexpression/knockdown ECM analysis\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution of nucleation with recombinant protein plus in vivo implantation, single lab\",\n      \"pmids\": [\"29745814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PD-L1 directly binds EIF3I and promotes cutaneous wound healing by downregulating IRS4; the EIF3I–PD-L1–IRS4 axis was identified by immunoprecipitation combined with mass spectrometry and validated by co-immunoprecipitation assays with in vivo and in vitro functional testing.\",\n      \"method\": \"Co-IP with mass spectrometry, co-immunoprecipitation validation, in vivo and in vitro functional assays for wound healing\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction identified by IP-MS and validated by Co-IP with functional in vivo testing, single lab\",\n      \"pmids\": [\"34293353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lenalidomide (via the E3 ligase adapter CRBN) recruits eIF3i but does not degrade it; instead, it sequesters eIF3i from the eIF3 complex. The binding interface on eIF3i was identified by a covalent lenalidomide probe and mass spectrometry. This sequestration drives effects on angiogenic markers, Akt1 phosphorylation, and antiangiogenesis phenotypes.\",\n      \"method\": \"Covalent chemical probe + mass spectrometry mapping of binding interface, chemical proteomics, Co-IP for eIF3 complex disruption, cell-based angiogenesis and Akt1 phosphorylation assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — covalent probe with mass spectrometry for interface mapping (Tier 1 chemical biology), functional validation in cells, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36325969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"eIF3i directly promotes PHGDH translation in colorectal cancer cells. METTL3-mediated m6A modification on PHGDH mRNA promotes its binding to eIF3i, leading to higher translational rate of PHGDH. PHGDH knockdown partially attenuates the excessive growth induced by eIF3i overexpression.\",\n      \"method\": \"Ribosome profiling, proteomics, m6A modification analysis, RIP assay for eIF3i-PHGDH mRNA binding, siRNA knockdown epistasis, in vivo tumor growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ribosome profiling plus RIP plus m6A analysis plus epistasis knockdown, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37611825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"lnc-TSPAN12 acts as a scaffold that enhances the SENP1-EIF3I interaction, inhibiting SUMOylation of EIF3I and preventing its ubiquitin-mediated degradation, thereby stabilizing EIF3I protein levels and activating Wnt/β-catenin signaling to promote EMT and HCC metastasis.\",\n      \"method\": \"Co-IP (EIF3I-SENP1 interaction), RNA pull-down, SUMOylation assay, ubiquitination assay, lncRNA knockdown/overexpression, in vivo metastasis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation/ubiquitination assays with Co-IP validation and in vivo functional testing, single lab\",\n      \"pmids\": [\"38374407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"eIF3i directly binds NELFCD mRNA and promotes its translation, independent of transcription. eIF3i-driven NELFCD upregulation facilitates EMT and invadopodia formation, promoting CRC metastasis. NELFCD knockdown abolishes the pro-metastatic effects of eIF3i overexpression.\",\n      \"method\": \"Polysome profiling, RNA-binding assays (RIP and RNA pull-down), in vitro migration/invasion assays, in vivo mouse metastatic models, epistasis knockdown\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA binding validated by RIP and RNA pull-down, polysome profiling, epistasis knockdown, single lab\",\n      \"pmids\": [\"41315067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss-of-function mutations in eIF3i (yeast ortholog) reduce translation of GFP reporters with both short and long unstructured 5′ UTRs to a similar extent as mutations in other scanning factors (eIF4A, Ded1, eIF4G, eIF4B, eIF3g), and severely diminish translation of reporters with structured 5′ UTRs. This is consistent with eIF3i facilitating mRNA scanning and secondary structure unwinding rather than being the rate-limiting helicase-driven translocase.\",\n      \"method\": \"GFP reporter assay in S. cerevisiae, loss-of-function mutations in eIF3i and comparison with other initiation factor mutants\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single reporter system, indirect inference about mechanism from comparative mutant analysis\",\n      \"pmids\": [\"bio_10.1101_2024.12.30.630811\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EIF3I (TRIP-1/eIF3-p36) is a WD40-repeat subunit of the eIF3 complex that functions both as a general translation initiation factor (stimulating 43S PIC scanning and mRNA translation) and as a selective translational regulator—directly binding specific mRNAs (VEGFA, PHGDH, NELFCD, COX-2) to enhance their translation; it also acts as a signaling hub that interacts with the TGF-β type II receptor (being phosphorylated by it to modulate Smad signaling), forms a complex with Akt1 to block PP2A-mediated dephosphorylation and sustain constitutive Akt1 activity, undergoes mTOR-mediated serine phosphorylation, and can be sequestered from the eIF3 complex by lenalidomide-bound CRBN, collectively explaining its roles in cell growth, angiogenesis, fibrosis, and oncogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3I (TRIP-1/eIF3-p36) is a WD40-repeat subunit of the eIF3 translation-initiation complex that operates both as a general initiation factor and as a selective translational regulator coupling growth and survival signaling to protein synthesis [#1, #5]. Genetic dissection of the yeast ortholog establishes that eIF3i stimulates linear 43S scanning of post-termination 40S ribosomes without affecting eIF3 integrity or 43S PIC formation [#1]. Beyond bulk initiation, eIF3i directly binds and selectively enhances translation of specific mRNAs—VEGFA under hypoxia downstream of HIF1A, PHGDH (whose binding is favored by METTL3-deposited m6A), and NELFCD—thereby promoting angiogenesis, metabolic rewiring, EMT, and metastasis [#5, #13, #15]. EIF3I also serves as a signaling hub: it associates with the TGF-\\u03b2 type II receptor and is phosphorylated by it to repress Smad-driven PAI-1 transcription [#0], and it binds the Akt1 kinase domain through its C-terminus to block PP2A-mediated dephosphorylation and sustain constitutive Akt1 activity that drives hepatocellular tumorigenesis and fibroblast-to-myofibroblast transdifferentiation [#3, #6]. Its oncogenic activity requires mTOR-dependent serine phosphorylation [#2], and its protein level is controlled by a SUMOylation/ubiquitination axis that, when stabilized, activates Wnt/\\u03b2-catenin signaling [#14]. Pharmacologically, CRBN-bound lenalidomide sequesters eIF3i from the eIF3 complex without degrading it, producing antiangiogenic effects [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the first signaling role for EIF3I beyond translation by showing it is a receptor-associated substrate that modulates TGF-\\u03b2 transcriptional output.\",\n      \"evidence\": \"Co-IP receptor association, PAI-1 promoter reporter assay, and deletion mutagenesis in transfected cells\",\n      \"pmids\": [\"9813058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological phosphorylation sites on EIF3I by TGF-\\u03b2RII not mapped\", \"Receptor-independent mechanism of Smad repression undefined\", \"Relationship to its eIF3 role unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected EIF3I to growth control by identifying mTOR-dependent serine phosphorylation as a requirement for its proliferative and transforming activity.\",\n      \"evidence\": \"Overexpression with rapamycin treatment, phosphorylation and anchorage-independent growth assays in cell lines\",\n      \"pmids\": [\"16929481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific serine residue(s) not identified\", \"Direct versus indirect mTOR phosphorylation not resolved\", \"Mechanistic link between phosphorylation and oncogenic output unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pinpointed the molecular contribution of eIF3i within initiation, showing it stimulates linear 40S scanning rather than complex assembly or PIC formation.\",\n      \"evidence\": \"WD40-repeat point mutation (Q258R) with in vivo translation rate, GCN4 reporter, and polysome analyses in yeast\",\n      \"pmids\": [\"20679478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of scanning stimulation by the WD40 domain unknown\", \"Generality to human eIF3I not directly tested\", \"No structural model of the scanning step\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a direct oncogenic mechanism in which EIF3I sustains Akt1 activity, and separately showed selective translational control of COX-2.\",\n      \"evidence\": \"Reciprocal Co-IP, C-terminal domain mapping, PP2A dephosphorylation assay, dominant-negative rescue, and tumorigenesis assays; polysome and \\u03b2-catenin/TCF4 reporter assays\",\n      \"pmids\": [\"23460382\", \"24056964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the EIF3I\\u2013Akt1 interface absent\", \"How EIF3I physically excludes PP2A unresolved\", \"Mechanism of selective COX-2 mRNA translation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established EIF3I as a HIF1A-induced selective translational regulator of VEGFA and as an Akt-acting node in fibrosis, broadening its physiological reach.\",\n      \"evidence\": \"ChIP, siRNA knockdown, polysome profiling, zebrafish mutant angiogenesis and xenograft models; fibroblast transdifferentiation with AKT epistasis\",\n      \"pmids\": [\"25147179\", \"24528651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA features conferring VEGFA selectivity unidentified\", \"Whether VEGFA binding is direct not fully resolved\", \"Smad-independent route to AKT activation in fibroblasts mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the EIF3I\\u2013Akt axis to metastasis by showing clusterin partners with EIF3I to drive MMP13 expression.\",\n      \"evidence\": \"Co-IP of CLU-EIF3I, invasion/metastasis assays, and CLU knockdown in HCC\",\n      \"pmids\": [\"25609201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect CLU\\u2013EIF3I binding not established\", \"No reciprocal interaction mapping\", \"Link between complex formation and MMP13 induction mechanistic gap\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed EIF3I selectively controls translation of pro-angiogenic effectors (VEGFR2/ERK) in endothelial cells and identified a physical interaction with VSV M protein affecting viral replication.\",\n      \"evidence\": \"siRNA knockdown, zebrafish mutant, proliferation/migration assays, Western blot; yeast two-hybrid, GST pull-down, co-localization, viral replication assay\",\n      \"pmids\": [\"28193911\", \"29173589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of VEGFR2/ERK mRNA selectivity unknown\", \"Functional consequence of VSV M binding incompletely defined\", \"Whether viral effect depends on the eIF3 complex unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a non-canonical extracellular function in which EIF3I/TRIP-1 nucleates hydroxyapatite in mineralized matrix.\",\n      \"evidence\": \"In vivo implantation, recombinant protein nucleation experiments, and TEM of mineral deposits\",\n      \"pmids\": [\"29745814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of secretion to the ECM unknown\", \"Relationship to its intracellular eIF3 role unexplained\", \"Domain mediating mineral nucleation unmapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a PD-L1\\u2013EIF3I\\u2013IRS4 axis linking EIF3I to wound healing.\",\n      \"evidence\": \"IP-MS discovery, Co-IP validation, and in vivo/in vitro wound-healing functional assays\",\n      \"pmids\": [\"34293353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"How EIF3I downregulates IRS4 mechanistically unclear\", \"Translation-dependence of the effect untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a druggable, non-degradative mechanism in which CRBN-bound lenalidomide sequesters eIF3i out of the eIF3 complex, with antiangiogenic consequences.\",\n      \"evidence\": \"Covalent lenalidomide probe with mass-spectrometry interface mapping, chemical proteomics, Co-IP for complex disruption, and cell-based assays\",\n      \"pmids\": [\"36325969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative effect on global translation not defined\", \"Selectivity of sequestration over other eIF3 subunits unaddressed\", \"In vivo relevance of the antiangiogenic effect untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected RNA modification to selective translation by showing METTL3-deposited m6A on PHGDH mRNA promotes its binding to eIF3i and enhanced translation.\",\n      \"evidence\": \"Ribosome profiling, proteomics, m6A analysis, RIP for eIF3i-PHGDH binding, and epistasis knockdown with in vivo tumor assays\",\n      \"pmids\": [\"37611825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether eIF3i directly reads m6A marks not resolved\", \"Structural basis of mRNA recognition unknown\", \"Breadth of m6A-dependent target set undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational control of EIF3I abundance, showing a SENP1/lnc-TSPAN12 axis blocks its SUMOylation-dependent degradation to activate Wnt/\\u03b2-catenin signaling.\",\n      \"evidence\": \"Co-IP, RNA pull-down, SUMOylation and ubiquitination assays, lncRNA manipulation, and in vivo metastasis assays\",\n      \"pmids\": [\"38374407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation site(s) on EIF3I not mapped\", \"E3 ligase mediating ubiquitination unidentified\", \"Link between EIF3I stabilization and Wnt activation mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added NELFCD to the set of directly bound mRNAs selectively translated by eIF3i to drive EMT and invadopodia formation in colorectal cancer.\",\n      \"evidence\": \"Polysome profiling, RIP and RNA pull-down, migration/invasion assays, in vivo metastasis models, and epistasis knockdown\",\n      \"pmids\": [\"41315067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence/structural determinants of NELFCD mRNA selectivity unknown\", \"Whether binding requires the full eIF3 complex untested\", \"Generalizable rules for eIF3i target selection still lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How eIF3i achieves selective recognition of specific mRNAs (VEGFA, PHGDH, NELFCD, COX-2) versus its general scanning role within eIF3 remains the central unresolved question.\",\n      \"evidence\": \"No single study reconciles target-selective binding with the WD40-domain scanning mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of human EIF3I bound to a target mRNA\", \"Determinants distinguishing selective targets from bulk mRNAs undefined\", \"Whether selective translation occurs within or outside the canonical eIF3 complex unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 13, 15]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [1, 5, 13, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 5, 13, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 13, 14, 15]}\n    ],\n    \"complexes\": [\"eIF3 complex\"],\n    \"partners\": [\"AKT1\", \"TGFBR2\", \"CLU\", \"CD274\", \"SENP1\", \"CRBN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}