{"gene":"EIF3C","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2013,"finding":"Human eIF4G binds to eIF3 through a surface comprised of eIF3c, eIF3d, and eIF3e subunits, identified by site-specific cross-linking. Two distinct eIF3-binding subdomains within eIF4G were identified, and both are required for efficient mRNA recruitment to the ribosome and stimulation of translation, as shown by a fluorescence anisotropy assay and an eIF4G-dependent translation assay.","method":"Site-specific cross-linking, fluorescence anisotropy, eIF4G-dependent translation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (cross-linking, fluorescence anisotropy, functional translation assay) in a single rigorous study directly mapping the eIF4G–eIF3c interaction","pmids":["24092755"],"is_preprint":false},{"year":2011,"finding":"The C-terminal PCI domain of eIF3c/NIP1 directly interacts with blades 1–3 of the small ribosomal protein RACK1/ASC1 on the 40S head, and the PCI domain also shows strong but unspecific RNA binding. Mutations disrupting the PCI domain reduce 40S-bound eIF3 and eIF5 in vivo, and deletion of ASC1 similarly reduces eIF3 association with ribosomes, indicating that eIF3c forms an intermolecular bridge between eIF3 and the 40S head via RACK1/ASC1 and likely 18S rRNA.","method":"In vivo ribosome association assays, site-directed mutagenesis, genetic interaction (ASC1 deletion), RNA binding assays, yeast genetics","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, in vivo ribosome fractionation, genetic epistasis, RNA binding) in a single study with rigorous controls","pmids":["22123745"],"is_preprint":false},{"year":2017,"finding":"The N-terminal domain (NTD) of eIF3c is divided into three parts (3c0, 3c1, 3c2): 3c0 binds eIF5 strongly and eIF1 weakly; 3c1 contacts eIF1 through Arg-53 and Leu-96; 3c2 faces 40S protein uS15/S13 to anchor eIF1 to the scanning pre-initiation complex (PIC). The 3c0:eIF5 interaction stabilizes the scanning PIC by precluding the inhibitory 3c0:eIF1 interaction, and upon start codon recognition, eIF5 interactions involving 3c0 facilitate eIF1 release.","method":"NMR, structural analysis, mutagenesis, in vitro binding assays, ribosome scanning assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural data combined with mutagenesis and functional PIC assembly/scanning assays in a single study","pmids":["28297669"],"is_preprint":false},{"year":2006,"finding":"The NF2 tumor suppressor schwannomin (merlin) directly interacts with eIF3c (p110 subunit). Schwannomin was most effective at inhibiting cellular proliferation when eIF3c was highly expressed, suggesting that schwannomin acts through eIF3c-mediated regulation of protein translation to suppress proliferation.","method":"Protein interaction screen (pulldown/co-immunoprecipitation), cellular proliferation assay, immunohistochemistry","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single pulldown/Co-IP identifying the interaction, with functional proliferation assay but limited mechanistic follow-up","pmids":["16497727"],"is_preprint":false},{"year":2013,"finding":"siRNA-mediated knockdown of eIF3c in multiple cancer cell lines decreases global protein synthesis and causes polysome run-off in vivo, demonstrating that eIF3c is essential for translation initiation. Knockdown also causes G0/G1 or G2/M cell cycle arrest in a cell-type-dependent manner, leading to reduced proliferation and cell death.","method":"siRNA knockdown, polysome profiling, cell cycle analysis by flow cytometry, cell viability assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome profiling directly demonstrates translation initiation function, combined with cell cycle phenotyping across multiple cell lines","pmids":["23623922"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function of Eif3c in mice causes sensitivity to Ptch1 dosage and disrupts Shh-mediated tissue patterning. Genome-wide eCLIP-seq shows eIF3 binds a pyrimidine-rich motif in subsets of 5'-UTRs; ribosome profiling in Eif3c loss-of-function embryos shows reduced translation of transcripts containing this motif, including Ptch1, demonstrating that eIF3c selectively controls translation of specific developmental signaling transcripts through their 5'-UTR pyrimidine-rich motifs.","method":"Mouse loss-of-function genetics, eCLIP-seq, ribosome profiling, in situ hybridization","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (eCLIP-seq, ribosome profiling, mouse genetics) replicated across multiple transcripts in a rigorous study","pmids":["34752747"],"is_preprint":false},{"year":2011,"finding":"Two Eif3c mutations (p.Arg303X and p.Leu568_Leu586del) in mouse cause a pleiotropic phenotype (anterior polydactyly, hypopigmentation) associated with ectopic Shh and Ptch1 expression and aberrant Gli3 processing in anterior limb buds, placing eIF3c upstream of SHH/GLI3 signaling in limb patterning.","method":"Mouse genetics (two Xs alleles), in situ hybridization, genetic mapping","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent loss-of-function alleles and ISH demonstrate pathway placement, but mechanism is inferred rather than biochemically defined","pmids":["21292980"],"is_preprint":false},{"year":2020,"finding":"The m6A reader YTHDF1 binds m6A-modified EIF3C mRNA and augments EIF3C translation in an m6A-dependent manner, thereby increasing overall translational output in ovarian cancer cells. Knockdown of YTHDF1 reduces EIF3C protein but not mRNA levels.","method":"m6A-seq, ribosome profiling, m6A-IP, RNA immunoprecipitation, YTHDF1 knockdown/overexpression, multi-omics","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal omics methods (m6A-seq, ribosome profiling, RIP) in a single study directly demonstrating translational regulation of EIF3C mRNA by YTHDF1","pmids":["31996915"],"is_preprint":false},{"year":2022,"finding":"circPDE5A interacts with the m6A writer WTAP (verified by RNA pulldown and mass spectrometry, and RIP assays), forming a circPDE5A-WTAP complex that blocks WTAP-dependent m6A methylation of EIF3C mRNA, thereby reducing EIF3C translation. Loss of circPDE5A increases EIF3C expression and activates the MAPK pathway, promoting prostate cancer metastasis.","method":"RNA pulldown with mass spectrometry, RNA immunoprecipitation, MeRIP-seq, functional in vitro and in vivo assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown with MS and RIP confirm interaction; MeRIP-seq identifies m6A on EIF3C mRNA; single lab study","pmids":["35650605"],"is_preprint":false},{"year":2017,"finding":"EIF3C knockdown in breast cancer cells activates the mTOR signaling pathway and leads to reduced proliferation and increased apoptosis, with altered phosphorylation of mTOR pathway components detected by antibody array and western blot.","method":"siRNA knockdown, antibody phosphoprotein array, western blotting, flow cytometry, colony formation assay","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway association inferred from phospho-antibody array after knockdown without direct mechanistic dissection of mTOR–eIF3c link","pmids":["28854163"],"is_preprint":false},{"year":2019,"finding":"EIF3C knockdown in osteosarcoma U-2OS cells leads to upregulation of CASP3/7, Chk1/2, and SAPK/JNK, indicating that eIF3c knockdown promotes apoptosis through the SAPK/JNK pathway.","method":"shRNA knockdown, PathScan antibody array, flow cytometry, MTT assay","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway association from antibody array after knockdown, no direct mechanistic rescue or epistasis","pmids":["30863090"],"is_preprint":false},{"year":2018,"finding":"EIF3C overexpression in HCC cells increases secretion of extracellular exosomes (confirmed by fluorescent labeling, electron microscopy, nanoparticle tracking, and exosome markers) and activates S100A11 expression, promoting tumor angiogenesis via exosome-mediated tube formation; exosome inhibitor GW4869 reverses these effects.","method":"EIF3C overexpression, PKH26 exosome labeling, electron microscopy, nanoparticle tracking analysis, tube formation assay, in vivo plug assay, exosome inhibitor treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods (EM, NTA, in vivo assay, inhibitor rescue) confirm exosome phenotype, but molecular mechanism linking eIF3c to exosome biogenesis is not defined biochemically","pmids":["29568350"],"is_preprint":false},{"year":2023,"finding":"RNA-seq analysis identified EIF3C as a target upregulated by CFH in RA monocytes and FLS; EIF3C knockdown under CFH+TNF-α stimulation promoted FLS migration and enhanced IL-6, IL-8, and MMP-3 expression, indicating that CFH-induced EIF3C upregulation mediates anti-inflammatory and anti-migratory effects in RA synoviocytes.","method":"RNA sequencing, siRNA knockdown, wound healing assay, transwell assay, ELISA","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inferred from RNA-seq and knockdown phenotype, no direct biochemical mechanism for CFH-EIF3C connection","pmids":["37996918"],"is_preprint":false},{"year":2025,"finding":"NMR backbone assignments of human eIF3c residues 166–266 (immediately N-terminal to the PINT/PCI domain) show this region is intrinsically disordered in solution, with short segments of modest α-helical or β-strand propensity. Three conserved FLKK motifs are located at junctions of transient structural elements, with Motif 3 in the subsegment with slightly greater structural propensity. This fragment encompasses the reported eIF1-binding site.","method":"Solution NMR (1H-15N HSQC, chemical shift index, temperature coefficients)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct NMR structural characterization of the eIF3c 166–266 fragment, but single preprint, no mutagenesis or binding validation yet","pmids":["bio_10.1101_2025.09.13.675972"],"is_preprint":true}],"current_model":"EIF3C (eIF3c/NIP1) is a core scaffold subunit of the eIF3 complex that promotes translation preinitiation complex (PIC) assembly by anchoring eIF1 to the 40S ribosome via its 3c1/3c2 NTD regions and RACK1/ASC1, bridges the mRNA cap-binding complex to the 40S through direct contacts with eIF4G (alongside eIF3d/e), controls scanning and start codon recognition through its 3c0 domain interactions with eIF5 and eIF1, binds pyrimidine-rich 5'-UTR motifs to selectively enhance translation of specific developmental signaling transcripts (including Ptch1), is itself regulated at the translational level by YTHDF1-mediated m6A reading and WTAP-dependent m6A methylation, and its knockdown causes global polysome run-off, cell cycle arrest, and apoptosis across diverse cell types."},"narrative":{"mechanistic_narrative":"EIF3C (eIF3c/NIP1) is a core scaffold subunit of the eIF3 complex that drives translation initiation by organizing the assembly and function of the 43S/48S preinitiation complex (PIC) [PMID:28297669, PMID:23623922]. Its C-terminal PCI domain forms an intermolecular bridge that tethers eIF3 to the 40S ribosomal head by contacting RACK1/ASC1 (and likely 18S rRNA), with PCI mutations or ASC1 loss reducing ribosome-associated eIF3 and eIF5 [PMID:22123745]. Its N-terminal domain is partitioned into 3c0/3c1/3c2 subregions that coordinate start-codon fidelity: 3c0 binds eIF5 strongly and eIF1 weakly, 3c1 and 3c2 anchor eIF1 to the scanning PIC, and competing 3c0:eIF5 versus 3c0:eIF1 interactions stabilize scanning and then facilitate eIF1 release upon start-codon recognition [PMID:28297669]. eIF3c additionally bridges the cap-binding machinery to the ribosome through a surface formed with eIF3d and eIF3e that engages two subdomains of eIF4G required for mRNA recruitment [PMID:24092755]. Beyond its general role, eIF3 binds a pyrimidine-rich 5'-UTR motif and selectively promotes translation of specific developmental signaling transcripts including Ptch1; loss of Eif3c disrupts Shh/Gli3-mediated tissue patterning, and global knockdown causes polysome run-off, cell-cycle arrest, and apoptosis [PMID:34752747, PMID:23623922, PMID:21292980]. EIF3C is itself controlled at the translational level by m6A: the reader YTHDF1 binds m6A-modified EIF3C mRNA to augment its translation, while a circPDE5A–WTAP interaction limits WTAP-dependent m6A methylation of EIF3C [PMID:31996915, PMID:35650605].","teleology":[{"year":2006,"claim":"Established the first functional link of eIF3c to growth control by showing the NF2 tumor suppressor merlin acts on it, framing eIF3c as a translation node relevant to proliferation.","evidence":"Protein interaction pulldown/Co-IP with merlin plus cellular proliferation assays","pmids":["16497727"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","No mapping of the merlin-binding region on eIF3c","Mechanistic link to translation inferred, not demonstrated"]},{"year":2011,"claim":"Defined how eIF3c physically anchors the entire eIF3 complex to the small ribosomal subunit, answering how eIF3 docks onto the 40S head.","evidence":"Yeast in vivo ribosome fractionation, PCI-domain mutagenesis, ASC1 deletion genetics, and RNA binding assays","pmids":["22123745"],"confidence":"High","gaps":["RNA binding by the PCI domain is nonspecific","Direct 18S rRNA contact inferred","Human ortholog interaction not directly tested here"]},{"year":2011,"claim":"Placed eIF3c genetically upstream of SHH/GLI3 signaling, the first in vivo evidence that eIF3c shapes a specific developmental pathway rather than only bulk translation.","evidence":"Two independent mouse loss-of-function alleles with in situ hybridization of Shh, Ptch1, and Gli3","pmids":["21292980"],"confidence":"Medium","gaps":["Mechanism of pathway control inferred, not biochemically defined","Whether the effect is direct on specific transcripts not yet shown"]},{"year":2013,"claim":"Demonstrated that eIF3c is required for global translation initiation, converting the genetic and interaction data into a direct ribosomal function.","evidence":"siRNA knockdown with polysome profiling, cell-cycle analysis, and viability assays across cancer cell lines","pmids":["23623922"],"confidence":"Medium","gaps":["Cell-cycle arrest phase is cell-type dependent","Does not separate scaffold versus regulatory contributions"]},{"year":2013,"claim":"Identified how the cap-binding machinery is bridged to eIF3, showing eIF3c (with eIF3d/e) provides the eIF4G docking surface needed for mRNA recruitment.","evidence":"Site-specific cross-linking, fluorescence anisotropy, and eIF4G-dependent translation assay","pmids":["24092755"],"confidence":"High","gaps":["Relative contributions of eIF3c versus eIF3d/e not resolved","Structural detail of the contact not defined"]},{"year":2017,"claim":"Resolved the domain logic of how eIF3c governs start-codon recognition by mapping 3c0/3c1/3c2 contacts with eIF1, eIF5, and the 40S.","evidence":"NMR, mutagenesis, and in vitro PIC assembly/scanning assays","pmids":["28297669"],"confidence":"High","gaps":["Dynamics of the 3c0 eIF5/eIF1 switch in cells not directly observed"]},{"year":2020,"claim":"Showed EIF3C is itself controlled translationally, with the m6A reader YTHDF1 boosting EIF3C protein output to raise overall translation.","evidence":"m6A-seq, ribosome profiling, RIP, and YTHDF1 knockdown/overexpression in ovarian cancer cells","pmids":["31996915"],"confidence":"High","gaps":["Specific m6A sites on EIF3C not pinpointed","Generality across tissues untested"]},{"year":2021,"claim":"Established that eIF3c confers transcript selectivity, binding a 5'-UTR pyrimidine-rich motif to preferentially translate developmental transcripts including Ptch1.","evidence":"Mouse loss-of-function genetics, eCLIP-seq, and ribosome profiling of embryos","pmids":["34752747"],"confidence":"High","gaps":["Whether eIF3c subunit alone or whole eIF3 confers motif recognition","Full transcript set under this control not enumerated"]},{"year":2022,"claim":"Extended translational regulation of EIF3C upstream, showing a circPDE5A–WTAP complex limits WTAP-dependent m6A methylation of EIF3C mRNA.","evidence":"RNA pulldown with mass spectrometry, RIP, MeRIP-seq, and in vitro/in vivo prostate cancer assays","pmids":["35650605"],"confidence":"Medium","gaps":["Single-lab study","Direct effect on EIF3C translation versus downstream MAPK output not fully separated"]},{"year":2025,"claim":"Began structural characterization of the eIF1-binding region, showing eIF3c residues 166–266 are intrinsically disordered with conserved FLKK motifs at transient structural junctions.","evidence":"Solution NMR backbone assignment of the human eIF3c 166–266 fragment (preprint)","pmids":["bio_10.1101_2025.09.13.675972"],"confidence":"Medium","gaps":["Single preprint with no mutagenesis or binding validation","Functional role of FLKK motifs untested"]},{"year":null,"claim":"How the cancer-associated phenotypes (mTOR/JNK signaling, exosome biogenesis, inflammatory responses) mechanistically connect to eIF3c's defined translation-scaffold activity remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Pathway links rest on knockdown phospho-array correlations without direct mechanism","No structural model of full-length eIF3c in the 48S PIC","Selectivity rules for motif-containing transcripts incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,8]}],"complexes":["eIF3 complex","43S/48S preinitiation complex"],"partners":["EIF4G1","EIF3D","EIF3E","RACK1","EIF1","EIF5","NF2","YTHDF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99613","full_name":"Eukaryotic translation initiation factor 3 subunit C","aliases":["Eukaryotic translation initiation factor 3 subunit 8","eIF3 p110"],"length_aa":913,"mass_kda":105.3,"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/Q99613/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3C"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":4.0},{"gene":"EIF3G","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"EIF3I","stoichiometry":0.2},{"gene":"EIF5","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"ENY2","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF3C","total_profiled":1310},"omim":[{"mim_id":"609596","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT K; EIF3K","url":"https://www.omim.org/entry/609596"},{"mim_id":"607379","title":"NF2, MOESIN-EZRIN-RADIXIN-LIKE (MERLIN) TUMOR SUPPRESSOR; NF2","url":"https://www.omim.org/entry/607379"},{"mim_id":"603916","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT C; EIF3C","url":"https://www.omim.org/entry/603916"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3C"},"hgnc":{"alias_symbol":["eIF3-p110"],"prev_symbol":["EIF3S8"]},"alphafold":{"accession":"Q99613","domains":[{"cath_id":"-","chopping":"52-163","consensus_level":"high","plddt":81.5587,"start":52,"end":163},{"cath_id":"-","chopping":"325-494","consensus_level":"high","plddt":81.1364,"start":325,"end":494}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99613","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99613-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99613-F1-predicted_aligned_error_v6.png","plddt_mean":71.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3C","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3C"},"sequence":{"accession":"Q99613","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99613.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99613/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99613"}},"corpus_meta":[{"pmid":"31996915","id":"PMC_31996915","title":"The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31996915","citation_count":592,"is_preprint":false},{"pmid":"24092755","id":"PMC_24092755","title":"Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24092755","citation_count":134,"is_preprint":false},{"pmid":"30362562","id":"PMC_30362562","title":"Overexpressed circ_0067934 acts as an oncogene to facilitate cervical cancer progression via the miR-545/EIF3C axis.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30362562","citation_count":95,"is_preprint":false},{"pmid":"22123745","id":"PMC_22123745","title":"The eIF3c/NIP1 PCI domain interacts with RNA and RACK1/ASC1 and promotes assembly of translation preinitiation complexes.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22123745","citation_count":63,"is_preprint":false},{"pmid":"35650605","id":"PMC_35650605","title":"circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35650605","citation_count":60,"is_preprint":false},{"pmid":"28297669","id":"PMC_28297669","title":"Molecular Landscape of the Ribosome Pre-initiation Complex during mRNA Scanning: Structural Role for eIF3c and Its Control by eIF5.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28297669","citation_count":58,"is_preprint":false},{"pmid":"29568350","id":"PMC_29568350","title":"EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29568350","citation_count":49,"is_preprint":false},{"pmid":"16497727","id":"PMC_16497727","title":"Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c).","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16497727","citation_count":39,"is_preprint":false},{"pmid":"28231410","id":"PMC_28231410","title":"Transcriptomic analyses of RNA-binding proteins reveal eIF3c promotes cell proliferation in hepatocellular carcinoma.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28231410","citation_count":35,"is_preprint":false},{"pmid":"23623922","id":"PMC_23623922","title":"eIF3c: a potential therapeutic target for cancer.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/23623922","citation_count":31,"is_preprint":false},{"pmid":"23733421","id":"PMC_23733421","title":"Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells.","date":"2013","source":"Journal of Zhejiang University. 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APP/HSPA1A/LMNB1 Axis.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/36157221","citation_count":7,"is_preprint":false},{"pmid":"32973416","id":"PMC_32973416","title":"Knockdown EIF3C Suppresses Cell Proliferation and Increases Apoptosis in Pancreatic Cancer Cell.","date":"2020","source":"Dose-response : a publication of International Hormesis Society","url":"https://pubmed.ncbi.nlm.nih.gov/32973416","citation_count":6,"is_preprint":false},{"pmid":"36147539","id":"PMC_36147539","title":"Targeting EIF3C to suppress the development and progression of nasopharyngeal carcinoma.","date":"2022","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36147539","citation_count":6,"is_preprint":false},{"pmid":"30863090","id":"PMC_30863090","title":"Knockdown of EIF3C promotes human U-2OS cells apoptosis through increased CASP3/7 and Chk1/2 by upregulating SAPK/JNK.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30863090","citation_count":6,"is_preprint":false},{"pmid":"40107112","id":"PMC_40107112","title":"Proteome of amino acids or IGF1-stimulated pacu muscle cells offers molecular insights and suggests FN1B and EIF3C as candidate markers of fish muscle growth.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/40107112","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.13.675972","title":"NMR assignments and secondary structure analysis of the eIF1-interacting fragment of human 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Two distinct eIF3-binding subdomains within eIF4G were identified, and both are required for efficient mRNA recruitment to the ribosome and stimulation of translation, as shown by a fluorescence anisotropy assay and an eIF4G-dependent translation assay.\",\n      \"method\": \"Site-specific cross-linking, fluorescence anisotropy, eIF4G-dependent translation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (cross-linking, fluorescence anisotropy, functional translation assay) in a single rigorous study directly mapping the eIF4G–eIF3c interaction\",\n      \"pmids\": [\"24092755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal PCI domain of eIF3c/NIP1 directly interacts with blades 1–3 of the small ribosomal protein RACK1/ASC1 on the 40S head, and the PCI domain also shows strong but unspecific RNA binding. Mutations disrupting the PCI domain reduce 40S-bound eIF3 and eIF5 in vivo, and deletion of ASC1 similarly reduces eIF3 association with ribosomes, indicating that eIF3c forms an intermolecular bridge between eIF3 and the 40S head via RACK1/ASC1 and likely 18S rRNA.\",\n      \"method\": \"In vivo ribosome association assays, site-directed mutagenesis, genetic interaction (ASC1 deletion), RNA binding assays, yeast genetics\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mutagenesis, in vivo ribosome fractionation, genetic epistasis, RNA binding) in a single study with rigorous controls\",\n      \"pmids\": [\"22123745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The N-terminal domain (NTD) of eIF3c is divided into three parts (3c0, 3c1, 3c2): 3c0 binds eIF5 strongly and eIF1 weakly; 3c1 contacts eIF1 through Arg-53 and Leu-96; 3c2 faces 40S protein uS15/S13 to anchor eIF1 to the scanning pre-initiation complex (PIC). The 3c0:eIF5 interaction stabilizes the scanning PIC by precluding the inhibitory 3c0:eIF1 interaction, and upon start codon recognition, eIF5 interactions involving 3c0 facilitate eIF1 release.\",\n      \"method\": \"NMR, structural analysis, mutagenesis, in vitro binding assays, ribosome scanning assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural data combined with mutagenesis and functional PIC assembly/scanning assays in a single study\",\n      \"pmids\": [\"28297669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The NF2 tumor suppressor schwannomin (merlin) directly interacts with eIF3c (p110 subunit). Schwannomin was most effective at inhibiting cellular proliferation when eIF3c was highly expressed, suggesting that schwannomin acts through eIF3c-mediated regulation of protein translation to suppress proliferation.\",\n      \"method\": \"Protein interaction screen (pulldown/co-immunoprecipitation), cellular proliferation assay, immunohistochemistry\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/Co-IP identifying the interaction, with functional proliferation assay but limited mechanistic follow-up\",\n      \"pmids\": [\"16497727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"siRNA-mediated knockdown of eIF3c in multiple cancer cell lines decreases global protein synthesis and causes polysome run-off in vivo, demonstrating that eIF3c is essential for translation initiation. Knockdown also causes G0/G1 or G2/M cell cycle arrest in a cell-type-dependent manner, leading to reduced proliferation and cell death.\",\n      \"method\": \"siRNA knockdown, polysome profiling, cell cycle analysis by flow cytometry, cell viability assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling directly demonstrates translation initiation function, combined with cell cycle phenotyping across multiple cell lines\",\n      \"pmids\": [\"23623922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function of Eif3c in mice causes sensitivity to Ptch1 dosage and disrupts Shh-mediated tissue patterning. Genome-wide eCLIP-seq shows eIF3 binds a pyrimidine-rich motif in subsets of 5'-UTRs; ribosome profiling in Eif3c loss-of-function embryos shows reduced translation of transcripts containing this motif, including Ptch1, demonstrating that eIF3c selectively controls translation of specific developmental signaling transcripts through their 5'-UTR pyrimidine-rich motifs.\",\n      \"method\": \"Mouse loss-of-function genetics, eCLIP-seq, ribosome profiling, in situ hybridization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (eCLIP-seq, ribosome profiling, mouse genetics) replicated across multiple transcripts in a rigorous study\",\n      \"pmids\": [\"34752747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two Eif3c mutations (p.Arg303X and p.Leu568_Leu586del) in mouse cause a pleiotropic phenotype (anterior polydactyly, hypopigmentation) associated with ectopic Shh and Ptch1 expression and aberrant Gli3 processing in anterior limb buds, placing eIF3c upstream of SHH/GLI3 signaling in limb patterning.\",\n      \"method\": \"Mouse genetics (two Xs alleles), in situ hybridization, genetic mapping\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent loss-of-function alleles and ISH demonstrate pathway placement, but mechanism is inferred rather than biochemically defined\",\n      \"pmids\": [\"21292980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The m6A reader YTHDF1 binds m6A-modified EIF3C mRNA and augments EIF3C translation in an m6A-dependent manner, thereby increasing overall translational output in ovarian cancer cells. Knockdown of YTHDF1 reduces EIF3C protein but not mRNA levels.\",\n      \"method\": \"m6A-seq, ribosome profiling, m6A-IP, RNA immunoprecipitation, YTHDF1 knockdown/overexpression, multi-omics\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal omics methods (m6A-seq, ribosome profiling, RIP) in a single study directly demonstrating translational regulation of EIF3C mRNA by YTHDF1\",\n      \"pmids\": [\"31996915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circPDE5A interacts with the m6A writer WTAP (verified by RNA pulldown and mass spectrometry, and RIP assays), forming a circPDE5A-WTAP complex that blocks WTAP-dependent m6A methylation of EIF3C mRNA, thereby reducing EIF3C translation. Loss of circPDE5A increases EIF3C expression and activates the MAPK pathway, promoting prostate cancer metastasis.\",\n      \"method\": \"RNA pulldown with mass spectrometry, RNA immunoprecipitation, MeRIP-seq, functional in vitro and in vivo assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown with MS and RIP confirm interaction; MeRIP-seq identifies m6A on EIF3C mRNA; single lab study\",\n      \"pmids\": [\"35650605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EIF3C knockdown in breast cancer cells activates the mTOR signaling pathway and leads to reduced proliferation and increased apoptosis, with altered phosphorylation of mTOR pathway components detected by antibody array and western blot.\",\n      \"method\": \"siRNA knockdown, antibody phosphoprotein array, western blotting, flow cytometry, colony formation assay\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway association inferred from phospho-antibody array after knockdown without direct mechanistic dissection of mTOR–eIF3c link\",\n      \"pmids\": [\"28854163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EIF3C knockdown in osteosarcoma U-2OS cells leads to upregulation of CASP3/7, Chk1/2, and SAPK/JNK, indicating that eIF3c knockdown promotes apoptosis through the SAPK/JNK pathway.\",\n      \"method\": \"shRNA knockdown, PathScan antibody array, flow cytometry, MTT assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway association from antibody array after knockdown, no direct mechanistic rescue or epistasis\",\n      \"pmids\": [\"30863090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EIF3C overexpression in HCC cells increases secretion of extracellular exosomes (confirmed by fluorescent labeling, electron microscopy, nanoparticle tracking, and exosome markers) and activates S100A11 expression, promoting tumor angiogenesis via exosome-mediated tube formation; exosome inhibitor GW4869 reverses these effects.\",\n      \"method\": \"EIF3C overexpression, PKH26 exosome labeling, electron microscopy, nanoparticle tracking analysis, tube formation assay, in vivo plug assay, exosome inhibitor treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods (EM, NTA, in vivo assay, inhibitor rescue) confirm exosome phenotype, but molecular mechanism linking eIF3c to exosome biogenesis is not defined biochemically\",\n      \"pmids\": [\"29568350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNA-seq analysis identified EIF3C as a target upregulated by CFH in RA monocytes and FLS; EIF3C knockdown under CFH+TNF-α stimulation promoted FLS migration and enhanced IL-6, IL-8, and MMP-3 expression, indicating that CFH-induced EIF3C upregulation mediates anti-inflammatory and anti-migratory effects in RA synoviocytes.\",\n      \"method\": \"RNA sequencing, siRNA knockdown, wound healing assay, transwell assay, ELISA\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inferred from RNA-seq and knockdown phenotype, no direct biochemical mechanism for CFH-EIF3C connection\",\n      \"pmids\": [\"37996918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMR backbone assignments of human eIF3c residues 166–266 (immediately N-terminal to the PINT/PCI domain) show this region is intrinsically disordered in solution, with short segments of modest α-helical or β-strand propensity. Three conserved FLKK motifs are located at junctions of transient structural elements, with Motif 3 in the subsegment with slightly greater structural propensity. This fragment encompasses the reported eIF1-binding site.\",\n      \"method\": \"Solution NMR (1H-15N HSQC, chemical shift index, temperature coefficients)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct NMR structural characterization of the eIF3c 166–266 fragment, but single preprint, no mutagenesis or binding validation yet\",\n      \"pmids\": [\"bio_10.1101_2025.09.13.675972\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EIF3C (eIF3c/NIP1) is a core scaffold subunit of the eIF3 complex that promotes translation preinitiation complex (PIC) assembly by anchoring eIF1 to the 40S ribosome via its 3c1/3c2 NTD regions and RACK1/ASC1, bridges the mRNA cap-binding complex to the 40S through direct contacts with eIF4G (alongside eIF3d/e), controls scanning and start codon recognition through its 3c0 domain interactions with eIF5 and eIF1, binds pyrimidine-rich 5'-UTR motifs to selectively enhance translation of specific developmental signaling transcripts (including Ptch1), is itself regulated at the translational level by YTHDF1-mediated m6A reading and WTAP-dependent m6A methylation, and its knockdown causes global polysome run-off, cell cycle arrest, and apoptosis across diverse cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3C (eIF3c/NIP1) is a core scaffold subunit of the eIF3 complex that drives translation initiation by organizing the assembly and function of the 43S/48S preinitiation complex (PIC) [#2, #4]. Its C-terminal PCI domain forms an intermolecular bridge that tethers eIF3 to the 40S ribosomal head by contacting RACK1/ASC1 (and likely 18S rRNA), with PCI mutations or ASC1 loss reducing ribosome-associated eIF3 and eIF5 [#1]. Its N-terminal domain is partitioned into 3c0/3c1/3c2 subregions that coordinate start-codon fidelity: 3c0 binds eIF5 strongly and eIF1 weakly, 3c1 and 3c2 anchor eIF1 to the scanning PIC, and competing 3c0:eIF5 versus 3c0:eIF1 interactions stabilize scanning and then facilitate eIF1 release upon start-codon recognition [#2]. eIF3c additionally bridges the cap-binding machinery to the ribosome through a surface formed with eIF3d and eIF3e that engages two subdomains of eIF4G required for mRNA recruitment [#0]. Beyond its general role, eIF3 binds a pyrimidine-rich 5'-UTR motif and selectively promotes translation of specific developmental signaling transcripts including Ptch1; loss of Eif3c disrupts Shh/Gli3-mediated tissue patterning, and global knockdown causes polysome run-off, cell-cycle arrest, and apoptosis [#5, #4, #6]. EIF3C is itself controlled at the translational level by m6A: the reader YTHDF1 binds m6A-modified EIF3C mRNA to augment its translation, while a circPDE5A–WTAP interaction limits WTAP-dependent m6A methylation of EIF3C [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first functional link of eIF3c to growth control by showing the NF2 tumor suppressor merlin acts on it, framing eIF3c as a translation node relevant to proliferation.\",\n      \"evidence\": \"Protein interaction pulldown/Co-IP with merlin plus cellular proliferation assays\",\n      \"pmids\": [\"16497727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"No mapping of the merlin-binding region on eIF3c\", \"Mechanistic link to translation inferred, not demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined how eIF3c physically anchors the entire eIF3 complex to the small ribosomal subunit, answering how eIF3 docks onto the 40S head.\",\n      \"evidence\": \"Yeast in vivo ribosome fractionation, PCI-domain mutagenesis, ASC1 deletion genetics, and RNA binding assays\",\n      \"pmids\": [\"22123745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA binding by the PCI domain is nonspecific\", \"Direct 18S rRNA contact inferred\", \"Human ortholog interaction not directly tested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed eIF3c genetically upstream of SHH/GLI3 signaling, the first in vivo evidence that eIF3c shapes a specific developmental pathway rather than only bulk translation.\",\n      \"evidence\": \"Two independent mouse loss-of-function alleles with in situ hybridization of Shh, Ptch1, and Gli3\",\n      \"pmids\": [\"21292980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of pathway control inferred, not biochemically defined\", \"Whether the effect is direct on specific transcripts not yet shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that eIF3c is required for global translation initiation, converting the genetic and interaction data into a direct ribosomal function.\",\n      \"evidence\": \"siRNA knockdown with polysome profiling, cell-cycle analysis, and viability assays across cancer cell lines\",\n      \"pmids\": [\"23623922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-cycle arrest phase is cell-type dependent\", \"Does not separate scaffold versus regulatory contributions\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified how the cap-binding machinery is bridged to eIF3, showing eIF3c (with eIF3d/e) provides the eIF4G docking surface needed for mRNA recruitment.\",\n      \"evidence\": \"Site-specific cross-linking, fluorescence anisotropy, and eIF4G-dependent translation assay\",\n      \"pmids\": [\"24092755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of eIF3c versus eIF3d/e not resolved\", \"Structural detail of the contact not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the domain logic of how eIF3c governs start-codon recognition by mapping 3c0/3c1/3c2 contacts with eIF1, eIF5, and the 40S.\",\n      \"evidence\": \"NMR, mutagenesis, and in vitro PIC assembly/scanning assays\",\n      \"pmids\": [\"28297669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the 3c0 eIF5/eIF1 switch in cells not directly observed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed EIF3C is itself controlled translationally, with the m6A reader YTHDF1 boosting EIF3C protein output to raise overall translation.\",\n      \"evidence\": \"m6A-seq, ribosome profiling, RIP, and YTHDF1 knockdown/overexpression in ovarian cancer cells\",\n      \"pmids\": [\"31996915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific m6A sites on EIF3C not pinpointed\", \"Generality across tissues untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that eIF3c confers transcript selectivity, binding a 5'-UTR pyrimidine-rich motif to preferentially translate developmental transcripts including Ptch1.\",\n      \"evidence\": \"Mouse loss-of-function genetics, eCLIP-seq, and ribosome profiling of embryos\",\n      \"pmids\": [\"34752747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether eIF3c subunit alone or whole eIF3 confers motif recognition\", \"Full transcript set under this control not enumerated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended translational regulation of EIF3C upstream, showing a circPDE5A–WTAP complex limits WTAP-dependent m6A methylation of EIF3C mRNA.\",\n      \"evidence\": \"RNA pulldown with mass spectrometry, RIP, MeRIP-seq, and in vitro/in vivo prostate cancer assays\",\n      \"pmids\": [\"35650605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct effect on EIF3C translation versus downstream MAPK output not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Began structural characterization of the eIF1-binding region, showing eIF3c residues 166–266 are intrinsically disordered with conserved FLKK motifs at transient structural junctions.\",\n      \"evidence\": \"Solution NMR backbone assignment of the human eIF3c 166–266 fragment (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.13.675972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single preprint with no mutagenesis or binding validation\", \"Functional role of FLKK motifs untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cancer-associated phenotypes (mTOR/JNK signaling, exosome biogenesis, inflammatory responses) mechanistically connect to eIF3c's defined translation-scaffold activity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway links rest on knockdown phospho-array correlations without direct mechanism\", \"No structural model of full-length eIF3c in the 48S PIC\", \"Selectivity rules for motif-containing transcripts incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"eIF3 complex\", \"43S/48S preinitiation complex\"],\n    \"partners\": [\"EIF4G1\", \"EIF3D\", \"EIF3E\", \"RACK1\", \"EIF1\", \"EIF5\", \"NF2\", \"YTHDF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}