{"gene":"FAM3C","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2010,"finding":"hnRNP E1 (encoded by PCBP1) binds a 33-nucleotide TGF-β-activated translation (BAT) element in the 3' UTR of ILEI mRNA and represses its translation. TGF-β signaling leads to phosphorylation of hnRNP E1 at Ser43 by PKBβ/Akt2, causing its release from the BAT element and translational de-repression of ILEI.","method":"RNA pulldown, site-directed mutagenesis of BAT element, phospho-specific antibodies, RNAi knockdown with translational reporter assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding assay, mutagenesis, kinase identification, functional EMT readout), replicated in lung cancer context (PMID:24072492)","pmids":["20154680"],"is_preprint":false},{"year":2006,"finding":"Stable overexpression of ILEI in mouse mammary epithelial cells (EpH4 and EpRas) induces EMT, tumor growth, and metastasis independently of TGFβ-R signaling; RNAi-mediated knockdown prevents and reverts TGFβ-dependent EMT and abrogates metastasis formation.","method":"Stable overexpression, RNAi knockdown, in vivo tumor/metastasis assays, expression profiling","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with in vivo metastasis endpoints, replicated across multiple studies","pmids":["16959614"],"is_preprint":false},{"year":2008,"finding":"ILEI cooperates with oncogenic Ras to cause TGF-β-independent EMT in hepatocytes; ILEI-induced PDGF/PDGF-R signaling is required for enhanced cell migration, nuclear accumulation of β-catenin, nuclear pY-Stat3, and accelerated lung metastasis growth, as shown by dominant-negative PDGF-R rescue experiments.","method":"Dominant-negative receptor expression, Western blotting for signaling intermediates, in vivo metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via dominant-negative receptor plus in vivo endpoint, single lab","pmids":["19015638"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of murine FAM3B PANDER reveals a globular β-β-α fold (two antiparallel β sheets lined by three short helices forming a water-filled cavity), inconsistent with the predicted four-helix bundle cytokine fold; the fold is conserved throughout the FAM3 superfamily including FAM3C/ILEI, indicating FAM3 proteins represent a distinct structural class of signaling molecules.","method":"X-ray crystallography (crystal structure of FAM3B PANDER as FAM3 family representative)","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional inference extended to FAM3C by fold conservation; later confirmed by direct FAM3C crystal structure (PMID:28751379)","pmids":["23333428"],"is_preprint":false},{"year":2014,"finding":"ILEI binds to the γ-secretase complex (specifically its presenilin subunit) and destabilizes the β-secretase-cleaved APP C-terminal fragment (the penultimate Aβ precursor), thereby reducing Aβ production without affecting Notch signaling or γ-secretase catalytic activity; TGF-β signaling induces neuronal ILEI expression; transgenic ILEI overexpression reduces brain Aβ burden and ameliorates memory deficits in AD model mice.","method":"Co-immunoprecipitation with γ-secretase complex, APP-CTF stability assays, transgenic mouse model, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing complex, biochemical substrate (APP-CTF) destabilization assay, in vivo transgenic rescue with functional (cognitive) endpoint","pmids":["24894631"],"is_preprint":false},{"year":2016,"finding":"The ubiquitin ligase UBE4A directly interacts with ILEI protein and mediates its polyubiquitination and proteasomal degradation. Mass spectrometry of FLAG-ILEI immunoprecipitates identified UBE4A and UBE3C as interactors; overexpression of UBE4A (but not UBE3C) destabilized ILEI; RNAi knockdown of UBE4A caused accumulation of ILEI; co-IP confirmed endogenous ILEI–UBE4A interaction.","method":"Mass spectrometry of immunoprecipitates, co-immunoprecipitation, proteasome inhibitor treatment (MG-132), RNAi, overexpression of ubiquitin ligases","journal":"IUBMB life","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS identification plus reciprocal co-IP plus functional ubiquitination assay with mutagenic specificity (UBE4A vs UBE3C), single lab","pmids":["27862841"],"is_preprint":false},{"year":2016,"finding":"FAM3C overexpression in hepatocytes upregulates HSF1 expression, which elevates calmodulin (CaM) protein by inducing CALM1 transcription, activating Akt in a Ca²⁺- and insulin-independent manner; this FAM3C-HSF1-CaM-Akt pathway suppresses gluconeogenesis via nuclear exclusion of FOXO1 and reduces lipid deposition.","method":"Adenoviral overexpression in hepatocytes and mouse liver, Western blotting, promoter/transcription assays, CaM-dependent pathway inhibition","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo overexpression with defined pathway intermediates, single lab, pathway rescue not shown","pmids":["28246289"],"is_preprint":false},{"year":2016,"finding":"Fam3c is expressed during osteoblast differentiation and overexpression reduces Runx2 expression at both mRNA and protein levels, inhibiting alkaline phosphatase activity; knockdown has the opposite effect. Fam3c is localized intracellularly in the cytoplasm during osteoblast differentiation and is not secreted, suggesting intracellular function in this context. Fam3c and TGF-β1 reciprocally regulate each other.","method":"siRNA knockdown, overexpression, RT-PCR, Western blot, immunofluorescence localization, alkaline phosphatase activity assay","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined molecular target (Runx2), direct localization experiment, single lab","pmids":["27914282"],"is_preprint":false},{"year":2016,"finding":"Fam3c knockout mice show decreased trabecular bone number in tibiae and increased cortical bone mineral density; knockout bone marrow cells display accelerated osteogenic differentiation and mineralization in vitro, establishing a functional role for Fam3c in osteoblast differentiation and bone homeostasis.","method":"Knockout mouse generation, micro-CT analysis, in vitro osteogenic differentiation of bone marrow stromal cells","journal":"BoneKEy reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined bone phenotype and in vitro cellular readout, single lab","pmids":["27087939"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of FAM3C/ILEI reveal a β-β-α fold inconsistent with interleukin classification; ILEI exists as monomers and covalent domain-swapped dimers formed by intramolecular-to-intermolecular disulfide isomerization at Cys185. Dimeric but not monomeric ILEI causes dose-dependent increase in EpRas cell invasiveness comparable to TGF-β.","method":"X-ray crystallography, analytical ultracentrifugation, disulfide bond analysis, cell invasion assay with purified monomers vs. dimers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biochemical dimer/monomer separation plus functional cell invasion assay directly linking dimerization to activity","pmids":["28751379"],"is_preprint":false},{"year":2017,"finding":"Covalent dimerization of ILEI via Cys185 is essential for EMT induction, tumor growth, and lung metastasis in vivo. Mutation C185A prevents dimerization without affecting secretion; C185A-expressing tumor cells fail to induce EMT or form large tumors/metastases in nude mice, whereas wild-type ILEI-expressing cells do. ILEI monomers and C185A mutants affect only cell motility, not full EMT.","method":"Cysteine mutagenesis (C185A), pulse-chase experiments, purified protein incubation with serum, in vivo xenograft/metastasis assays, scratch assay and time-lapse microscopy","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with biochemical dimerization assay plus in vivo tumor/metastasis functional endpoint, corroborates parallel structural study (PMID:28751379)","pmids":["28837266"],"is_preprint":false},{"year":2017,"finding":"FAM3C functions as a secreted hepatokine; conditioned medium from FAM3C-overexpressing hepatocytes induces Akt phosphorylation in recipient cells, and this is blocked by anti-FAM3C antibodies. Recombinant FAM3C protein activates Akt in a HSF1- and CaM-dependent manner, represses FOXO1 nuclear activity and gluconeogenesis independently of insulin in type 1 diabetic mice.","method":"Conditioned medium transfer, anti-FAM3C antibody neutralization, recombinant protein treatment, hepatocyte culture with signaling readouts, in vivo STZ-diabetic mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody neutralization confirms secreted function, recombinant protein with defined pathway readouts, single lab","pmids":["29285313"],"is_preprint":false},{"year":2018,"finding":"ILEI is transcriptionally up-regulated by USF-1 (an E-box-binding bHLH transcription factor) through direct binding of USF-1 to the ILEI promoter. UV-mediated USF-1 activation increases ILEI expression; shRNA knockdown of USF-1 decreases ILEI transcription and tumor cell migration. shRNA knockdown of ILEI in melanoma attenuates lung colonization but not primary tumor formation.","method":"shRNA knockdown, promoter reporter assay, chromatin immunoprecipitation (direct USF-1–promoter interaction), in vivo lung colonization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes direct promoter binding, functional shRNA with in vivo endpoint, single lab","pmids":["29871931"],"is_preprint":false},{"year":2019,"finding":"ILEI signals through LIFR (leukemia inhibitory factor receptor) as its receptor; FAM3C/LIFR interaction in the extracellular space activates STAT3 signaling to drive EMT and breast cancer stem cell (BCSC) formation. Reduction of either ILEI or LIFR reduces tumor growth, tumor-initiating cells, and metastasis in vivo.","method":"Co-immunoprecipitation (ILEI–LIFR interaction), RNAi knockdown of ILEI and LIFR, in vivo orthotopic tumor assays, STAT3 phosphorylation readout","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying receptor, loss-of-function for both ligand and receptor with in vivo tumor/metastasis endpoints, replicated in renal fibrosis context (PMID:35093095)","pmids":["30692635"],"is_preprint":false},{"year":2019,"finding":"FAM3C activates a YY1–HSF1 signaling axis to promote proliferation and migration of breast cancer cells; YY1 directly activates HSF1 transcription; FAM3C inhibition represses TGF-β-induced HSF1 activation and downstream HSF1-Akt-Cyclin D1 pathway activity. YY1 and HSF1 had little effect on FAM3C expression itself.","method":"siRNA knockdown, overexpression, Western blotting, promoter reporter assay for HSF1 by YY1, TGF-β stimulation","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay for YY1→HSF1 direct activation, epistatic ordering via sequential knockdown, single lab","pmids":["30887707"],"is_preprint":false},{"year":2021,"finding":"Transcriptional downregulation of FAM3C in the Alzheimer's brain is mediated by reduced nuclear levels and impaired genomic DNA binding of SP1 and EBF1. Basal FAM3C promoter activity requires SP1 and EBF1; SMAD1 is an inducible transcriptional activator and KLF6 is a transcriptional repressor of FAM3C. Genomic deletion of the basal promoter sequence in HEK293 and Neuro-2a cells markedly reduced FAM3C expression.","method":"Promoter deletion/reporter assays, CRISPR genomic deletion, promoter DNA-binding assays with nuclear extracts from AD and control brains, expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR promoter deletion plus direct DNA-binding assay with disease-relevant nuclear extracts, single lab","pmids":["34378027"],"is_preprint":false},{"year":2021,"finding":"FAM3C/ILEI is co-amplified with MET on chromosome 7q31; ILEI knockdown impairs both c-MET-independent and c-MET-dependent cancer cell invasion but does not affect proliferation; c-MET inhibition reduces ILEI secretion; ILEI knockdown prevents c-MET-signaling-induced elevated MMP-2 and MMP-9 expression and secretion; combined ILEI knockdown plus c-MET inhibition reduces invasive tumor xenograft growth.","method":"Copy number analysis, shRNA knockdown, MMP ELISA/Western blot, invasion assay, in vivo xenograft tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway placement of ILEI downstream of c-MET for MMP regulation plus in vivo endpoint, single lab","pmids":["33596971"],"is_preprint":false},{"year":2021,"finding":"Extracellular release of ILEI and Aβ is dependent on neuronal activation via tetanus toxin-sensitive synaptic vesicle exocytosis; ILEI and Aβ are released from distinct synapse subpopulations; AMPA-receptor activation causes opposing changes in extracellular ILEI and Aβ levels; spontaneous ILEI and Aβ fluctuations are inversely correlated, supporting ILEI as a negative regulator of Aβ production in specific synapse types.","method":"In vivo microdialysis in APP-knockin mice, ILEI-specific ELISA, selective synaptic receptor pharmacology, tetanus toxin treatment","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo microdialysis with pharmacological manipulation of distinct synaptic receptor subsets, single lab","pmids":["33492290"],"is_preprint":false},{"year":2022,"finding":"Human FAM3C can substitute for the Fam3L2 domain of C. elegans FAMP-1 in AFD neurons to rescue memory-based thermotaxis behavior in famp-1 mutants; in vitro assays show that FAM3C (like the Fam3L2 domain) can bind carbohydrates similarly to the stem domain of POMGnT1, suggesting a carbohydrate-binding activity.","method":"In vivo rescue of C. elegans thermotaxis (neuron-specific expression), in vitro carbohydrate-binding assay","journal":"PNAS nexus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue in an orthologous system plus in vitro carbohydrate binding assay, single lab","pmids":["36712359"],"is_preprint":false},{"year":2022,"finding":"ILEI promotes renal tubular EMT by binding and activating LIFR (co-immunoprecipitation in HK2 cells), with downstream phosphorylation of Akt and ERK; ILEI knockdown in the UUO mouse model of renal fibrosis reduced EMT markers and fibrosis.","method":"Co-immunoprecipitation (ILEI–LIFR), Western blotting for pAkt/pERK, shRNA knockdown in UUO mouse model, in vitro transwell/WB assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirms ILEI–LIFR interaction with defined downstream signaling, in vivo UUO model, single lab; consistent with PMID:30692635","pmids":["35093095"],"is_preprint":false},{"year":2023,"finding":"TGF-β1 from tumor cells induces neutrophils to produce FAM3C via Smad2/3 signaling; FAM3C then promotes tumor cell EMT through JNK-ZEB1/Snail signaling; enhanced neutrophil–tumor cell crosstalk also requires integrin α6β1/α6β4 interaction with CD151.","method":"Co-culture experiments, Smad2/3 pathway inhibition, JNK inhibition, Western blotting for ZEB1/Snail, in vivo tumor-bearing mouse model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined paracrine signaling pathway with pharmacological pathway inhibition and in vivo model, single lab","pmids":["37056931"],"is_preprint":false},{"year":2023,"finding":"FAM3C drives a novel oncogenic signaling mode via extracellular vesicles (EVs): FAM3C in tumor-derived EVs is taken up by recipient cells and activates oncogenic signaling through a novel interaction with the Ras-related protein RalA, triggering downstream Src/STAT3 cascade activation, phenocopying endogenous FAM3C overexpression.","method":"EV proteomic mass spectrometry, co-immunoprecipitation (FAM3C–RalA), EV transfer to recipient cells, Src/STAT3 signaling readouts, in vivo metastasis assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP plus functional EV transfer assay with defined signaling readout, single lab","pmids":["36632230"],"is_preprint":false},{"year":2023,"finding":"PCBP1 (hnRNP E1) upregulates LIFR transcription at the LIFR promoter; FAM3C participates in transcriptional regulation of LIFR; downstream TWIST1 transcription factor maintains LIFR expression; FAM3C/LIFR/STAT3 signaling forms a feed-forward loop promoting BCSC invasion, migration, and self-renewal.","method":"Promoter reporter assay, PCBP1 knockdown, bioinformatic transcriptomic analysis, cell invasion/migration assays","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay plus functional BCSC assays, single lab; extends PMID:30692635","pmids":["37927213"],"is_preprint":false},{"year":2023,"finding":"ILEI overexpression in keratinocytes triggers ERK and Akt signaling, which activates STAT3 via Ser727 phosphorylation, driving psoriasiform hyperproliferation, impaired epidermal differentiation, and neutrophil recruitment. Keratinocyte-specific ILEI deletion ameliorates TPA-induced skin inflammation. Pharmacological inhibition of urokinase reduces ILEI secretion and psoriasiform symptoms.","method":"Inducible keratinocyte-specific ILEI transgenic mice (K5-ILEIind), keratinocyte-specific knockout, TPA challenge, Western blotting for pERK/pAkt/pSTAT3, urokinase inhibitor treatment","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal transgenic overexpression and tissue-specific KO with defined signaling mechanism, in vivo phenotype, and pharmacological rescue, single lab with multiple orthogonal approaches","pmids":["37226685"],"is_preprint":false},{"year":2024,"finding":"FAM3C expression in cancer-associated adipocytes (CAAs) is driven by TGF-β signaling from breast cancer cells; FAM3C in CAAs suppresses adipocyte-mesenchymal transition and fibrosis within the TME; FAM3C knockdown in CAAs inhibits primary and metastatic tumor growth in a genetically engineered mouse model.","method":"TGF-β neutralizing antibody treatment, adipocyte co-culture, FAM3C knockdown in CAAs, genetically engineered mouse model of breast cancer, tumor growth assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody neutralization establishes TGF-β as upstream driver, in vivo GEMM with tissue-specific knockdown, single lab","pmids":["38117489"],"is_preprint":false},{"year":2026,"finding":"FAM3C is retained in the Golgi apparatus through anchoring of its signal peptide into the membrane before the signal peptide and pro-peptide are processed and removed; while Golgi-retained, FAM3C alters Golgi morphology and affects protein secretion and invasive potential of TNBC cells.","method":"Subcellular fractionation, live-cell imaging, signal peptide mutagenesis, Golgi morphology assay, secretion and invasion assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (altered secretion and invasion), single lab, peer-reviewed","pmids":["41247074"],"is_preprint":false},{"year":2026,"finding":"USP33 acts as a deubiquitinase for eEF1A1, stabilizing eEF1A1 protein and thereby promoting ILEI protein synthesis; this USP33/eEF1A1/ILEI axis drives EMT and lenvatinib resistance in hepatocellular carcinoma.","method":"CRISPR KO screen, transcriptome sequencing, proteomic analysis, deubiquitinase activity assays, Western blotting for eEF1A1 stability","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen followed by proteomic identification plus deubiquitinase functional assay placing eEF1A1 upstream of ILEI translation, single lab","pmids":["42144151"],"is_preprint":false},{"year":2010,"finding":"FAM3C/XFAM3C is involved in retinal laminar formation in Xenopus: overexpression causes retinal laminar disorganization and increased eye size; morpholino-mediated loss-of-function causes photoreceptor cell dislocation without affecting cellular differentiation.","method":"Xenopus gain-of-function overexpression and morpholino antisense loss-of-function, retinal histology","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function in Xenopus with defined tissue-level phenotype, single lab","pmids":["20059962"],"is_preprint":false}],"current_model":"FAM3C/ILEI is a secreted cytokine-like protein with a β-β-α fold (not a four-helix bundle) that exists as monomers and covalent domain-swapped dimers (via Cys185); the dimer is the active species for EMT induction and metastasis. Its translation is repressed by hnRNP E1/PCBP1 binding a BAT element in its 3' UTR, and is de-repressed when TGF-β signaling triggers Akt2-mediated phosphorylation of hnRNP E1 at Ser43. Once secreted, ILEI signals through LIFR to activate STAT3 (driving EMT and breast cancer stem cell formation), and through RalA to activate Src/STAT3 when delivered via extracellular vesicles; it also activates ERK/Akt pathways in multiple contexts. Intracellularly, FAM3C is retained in the Golgi via its signal peptide, where it modulates Golgi morphology and protein secretion. Its protein stability is regulated post-translationally by the ubiquitin ligase UBE4A (mediating proteasomal degradation) and by the deubiquitinase USP33 acting via eEF1A1 to enhance ILEI synthesis. In neurons, ILEI binds the γ-secretase complex and destabilizes the APP C-terminal fragment to suppress Aβ production without inhibiting γ-secretase activity, and is released from synaptic vesicles in an activity-dependent manner. FAM3C also functions as a hepatokine activating an HSF1-CaM-Akt axis to suppress gluconeogenesis, and regulates osteoblast differentiation by suppressing Runx2."},"narrative":{"mechanistic_narrative":"FAM3C/ILEI is a secreted signaling protein with a distinct β-β-α fold that drives epithelial-to-mesenchymal transition (EMT), tumor growth, and metastasis [PMID:16959614, PMID:28751379]. Structurally it belongs to a distinct class of FAM3 superfamily molecules rather than the four-helix-bundle cytokines [PMID:23333428, PMID:28751379], and it exists as monomers and covalent domain-swapped dimers formed via disulfide isomerization at Cys185; the dimer is the active species, and the C185A mutant retains secretion but fails to induce EMT, tumor growth, or metastasis in vivo [PMID:28751379, PMID:28837266]. ILEI signals extracellularly through the receptor LIFR to activate STAT3, driving EMT and breast cancer stem cell formation, and the same ILEI/LIFR/STAT3 axis operates in renal tubular EMT and fibrosis [PMID:30692635, PMID:35093095]; it also activates ERK/Akt cascades in multiple contexts, including keratinocyte hyperproliferation in psoriasiform inflammation [PMID:35093095, PMID:37226685]. When delivered in extracellular vesicles, FAM3C engages RalA to trigger Src/STAT3 signaling [PMID:36632230]. Its output is tightly controlled at multiple levels: TGF-β signaling de-represses ILEI translation by driving Akt2-mediated phosphorylation of hnRNP E1/PCBP1 (Ser43), releasing it from a BAT element in the 3' UTR [PMID:20154680]; transcription is governed by USF-1, SP1/EBF1, SMAD1, and KLF6 [PMID:29871931, PMID:34378027]; and protein levels are set post-translationally by UBE4A-mediated proteasomal degradation and by a USP33–eEF1A1 axis that promotes ILEI synthesis [PMID:27862841, PMID:42144151]. Beyond cancer, FAM3C is multifunctional: in neurons it binds the γ-secretase complex (presenilin) and destabilizes the APP C-terminal fragment to suppress Aβ production without inhibiting catalysis, and is released in an activity-dependent manner from synaptic vesicles [PMID:24894631, PMID:33492290]; as a hepatokine it activates an HSF1–calmodulin–Akt axis that excludes FOXO1 from the nucleus to suppress gluconeogenesis [PMID:28246289, PMID:29285313]; and it regulates osteoblast differentiation by suppressing Runx2 and bone homeostasis in knockout mice [PMID:27914282, PMID:27087939]. Intracellularly, FAM3C is retained in the Golgi via its signal peptide, where it modulates Golgi morphology and protein secretion [PMID:41247074].","teleology":[{"year":2006,"claim":"Established that ILEI is a causal driver of EMT and metastasis rather than a bystander marker, by demonstrating reciprocal gain- and loss-of-function effects independent of TGF-β receptor signaling.","evidence":"Stable overexpression and RNAi knockdown in mouse mammary epithelial cells with in vivo tumor/metastasis endpoints","pmids":["16959614"],"confidence":"High","gaps":["Receptor and downstream signaling not yet identified","Molecular form of active ILEI unknown"]},{"year":2008,"claim":"Placed ILEI upstream of PDGF/PDGF-R signaling in driving TGF-β-independent EMT, linking it to β-catenin and Stat3 nuclear accumulation.","evidence":"Dominant-negative PDGF-R rescue in Ras-transformed hepatocytes with in vivo metastasis assays","pmids":["19015638"],"confidence":"Medium","gaps":["Direct ILEI receptor not defined","PDGF-R activation mechanism by ILEI unclear"]},{"year":2010,"claim":"Solved how TGF-β controls ILEI output post-transcriptionally, identifying a translational switch governed by hnRNP E1 phosphorylation.","evidence":"RNA pulldown, BAT element mutagenesis, phospho-specific antibodies and translational reporters","pmids":["20154680"],"confidence":"High","gaps":["Does not address transcriptional regulation","Kinetics relative to secretion not resolved"]},{"year":2010,"claim":"Extended FAM3C function to vertebrate development, implicating it in retinal lamination.","evidence":"Xenopus overexpression and morpholino loss-of-function with retinal histology","pmids":["20059962"],"confidence":"Medium","gaps":["Molecular mechanism in retina unknown","No receptor or signaling pathway defined"]},{"year":2013,"claim":"Reclassified the FAM3 superfamily structurally, showing a β-β-α fold rather than the predicted cytokine fold, redefining ILEI as a distinct class of signaling molecule.","evidence":"X-ray crystallography of FAM3B PANDER with fold conservation inferred for FAM3C","pmids":["23333428"],"confidence":"High","gaps":["Direct FAM3C structure not yet solved","Functional consequence of the fold not addressed"]},{"year":2014,"claim":"Revealed a non-oncogenic neuronal role, showing ILEI binds γ-secretase and destabilizes APP-CTF to suppress Aβ without blocking catalysis.","evidence":"Reciprocal co-IP, APP-CTF stability assays, transgenic AD mouse rescue with cognitive endpoints","pmids":["24894631"],"confidence":"High","gaps":["Mechanism of CTF destabilization unclear","Relationship to secreted/EMT functions not connected"]},{"year":2016,"claim":"Identified UBE4A as a direct E3 ligase controlling ILEI protein stability via proteasomal degradation.","evidence":"MS of immunoprecipitates, reciprocal co-IP, MG-132, ubiquitin ligase overexpression and RNAi","pmids":["27862841"],"confidence":"High","gaps":["Ubiquitination sites not mapped","Physiological contexts regulating UBE4A activity unknown"]},{"year":2016,"claim":"Defined FAM3C as a hepatic regulator of glucose metabolism via an HSF1-CaM-Akt axis suppressing gluconeogenesis.","evidence":"Adenoviral overexpression in hepatocytes and mouse liver with transcription/pathway readouts","pmids":["28246289"],"confidence":"Medium","gaps":["Receptor mediating hepatic FAM3C signaling not defined","Pathway rescue not shown"]},{"year":2016,"claim":"Established FAM3C as a regulator of osteoblast differentiation acting through suppression of Runx2, with a non-secreted intracellular localization in this context.","evidence":"Reciprocal knockdown/overexpression, immunofluorescence localization, alkaline phosphatase assays","pmids":["27914282"],"confidence":"Medium","gaps":["Mechanism linking FAM3C to Runx2 unknown","Reconciliation of secreted vs intracellular roles unresolved"]},{"year":2016,"claim":"Confirmed an in vivo role in bone homeostasis, showing Fam3c knockout alters trabecular and cortical bone and accelerates osteogenic differentiation.","evidence":"Knockout mice, micro-CT, in vitro osteogenic differentiation of marrow stromal cells","pmids":["27087939"],"confidence":"Medium","gaps":["Cell-autonomous vs systemic contributions not separated","Molecular pathway in vivo not defined"]},{"year":2017,"claim":"Directly determined the FAM3C structure and identified covalent domain-swapped dimerization at Cys185 as the active species for invasion.","evidence":"X-ray crystallography, analytical ultracentrifugation, disulfide analysis, monomer vs dimer invasion assays","pmids":["28751379"],"confidence":"High","gaps":["Trigger for dimerization in vivo unclear","Receptor recognition of dimer not addressed"]},{"year":2017,"claim":"Demonstrated that Cys185 dimerization is essential for full EMT and metastasis in vivo, separating dimer-driven EMT from monomer-driven motility.","evidence":"C185A mutagenesis, pulse-chase, in vivo xenograft/metastasis assays, motility imaging","pmids":["28837266"],"confidence":"High","gaps":["Why monomers retain only motility activity unexplained","Dimer-specific signaling not mapped"]},{"year":2017,"claim":"Confirmed FAM3C acts as a bona fide secreted hepatokine by antibody neutralization and recombinant protein activity on Akt and gluconeogenesis.","evidence":"Conditioned medium transfer, anti-FAM3C neutralization, recombinant protein, STZ-diabetic mice","pmids":["29285313"],"confidence":"Medium","gaps":["Receptor for hepatokine signaling unidentified","Single lab"]},{"year":2018,"claim":"Identified USF-1 as a direct transcriptional activator of ILEI linking stress (UV) to ILEI-driven tumor cell migration and colonization.","evidence":"ChIP, promoter reporter, shRNA knockdown, in vivo lung colonization","pmids":["29871931"],"confidence":"Medium","gaps":["Interplay with translational control not addressed","Other promoter inputs not yet defined"]},{"year":2019,"claim":"Identified LIFR as the receptor for ILEI, linking it to STAT3 activation, EMT, and breast cancer stem cell formation.","evidence":"Reciprocal co-IP, RNAi of ligand and receptor, orthotopic tumor assays, STAT3 readout","pmids":["30692635"],"confidence":"High","gaps":["Stoichiometry and dimer-receptor interaction not resolved","Co-receptor requirements unknown"]},{"year":2019,"claim":"Defined a YY1-HSF1-Akt-Cyclin D1 axis downstream of TGF-β and FAM3C promoting breast cancer proliferation and migration.","evidence":"Sequential knockdown/overexpression, promoter reporter for YY1→HSF1, TGF-β stimulation","pmids":["30887707"],"confidence":"Medium","gaps":["Direct vs indirect role of FAM3C in this axis unclear","Connection to LIFR/STAT3 not integrated"]},{"year":2021,"claim":"Mapped the transcriptional circuit controlling basal and disease-altered FAM3C expression in the brain (SP1/EBF1 basal, SMAD1 inducer, KLF6 repressor).","evidence":"Promoter deletion/reporter, CRISPR genomic deletion, DNA-binding assays with AD brain nuclear extracts","pmids":["34378027"],"confidence":"Medium","gaps":["Causal link of reduced FAM3C to AD pathology not established","Single lab"]},{"year":2021,"claim":"Showed activity-dependent synaptic release of ILEI and inverse coupling with Aβ, supporting ILEI as a negative regulator of Aβ in specific synapses.","evidence":"In vivo microdialysis in APP-knockin mice, ILEI ELISA, synaptic receptor pharmacology, tetanus toxin","pmids":["33492290"],"confidence":"Medium","gaps":["Molecular basis of synapse-subtype specificity unknown","Mechanism connecting release to CTF destabilization unclear"]},{"year":2021,"claim":"Positioned ILEI downstream of c-MET for MMP-2/9-driven invasion and showed it is co-amplified with MET, identifying a co-targetable axis.","evidence":"Copy number analysis, shRNA, MMP assays, invasion and in vivo xenograft assays","pmids":["33596971"],"confidence":"Medium","gaps":["Direct vs indirect MET-ILEI relationship unresolved","Mechanism of MET-dependent ILEI secretion unclear"]},{"year":2022,"claim":"Generalized the ILEI/LIFR/Akt/ERK axis beyond cancer to renal tubular EMT and fibrosis.","evidence":"Co-IP in HK2 cells, pAkt/pERK Western blot, shRNA in UUO mouse model","pmids":["35093095"],"confidence":"Medium","gaps":["Receptor stoichiometry unaddressed","Single lab"]},{"year":2022,"claim":"Provided cross-species evidence for a conserved FAM3C carbohydrate-binding activity by rescuing C. elegans neuronal behavior.","evidence":"C. elegans thermotaxis rescue with neuron-specific expression, in vitro carbohydrate-binding assay","pmids":["36712359"],"confidence":"Medium","gaps":["Physiological carbohydrate ligand in mammals unknown","Relevance to secreted signaling unclear"]},{"year":2023,"claim":"Uncovered an extracellular-vesicle-mediated signaling mode in which FAM3C engages RalA to drive Src/STAT3 oncogenic signaling.","evidence":"EV proteomics, FAM3C-RalA co-IP, EV transfer, Src/STAT3 readouts, in vivo metastasis","pmids":["36632230"],"confidence":"Medium","gaps":["How extracellular FAM3C accesses intracellular RalA unresolved","Relationship to LIFR pathway unclear"]},{"year":2023,"claim":"Defined a paracrine route in which tumor-derived TGF-β induces neutrophil FAM3C that promotes tumor EMT via JNK-ZEB1/Snail.","evidence":"Co-culture, Smad2/3 and JNK inhibition, ZEB1/Snail Western blot, in vivo tumor model","pmids":["37056931"],"confidence":"Medium","gaps":["Receptor mediating neutrophil-derived FAM3C signaling not defined","Integrin-CD151 contribution mechanistically unresolved"]},{"year":2023,"claim":"Established a non-cancer inflammatory role, with ILEI driving psoriasiform keratinocyte hyperproliferation via ERK/Akt-STAT3(Ser727).","evidence":"Inducible keratinocyte transgenic and knockout mice, TPA challenge, pERK/pAkt/pSTAT3 Western, urokinase inhibition","pmids":["37226685"],"confidence":"High","gaps":["Receptor in keratinocytes not defined","Role of dimerization in this context not tested"]},{"year":2023,"claim":"Added a feed-forward transcriptional loop in which PCBP1 and FAM3C upregulate LIFR with TWIST1 maintenance, reinforcing BCSC properties.","evidence":"Promoter reporter, PCBP1 knockdown, transcriptomic analysis, invasion/migration assays","pmids":["37927213"],"confidence":"Medium","gaps":["Mechanism by which FAM3C influences LIFR transcription unclear","Single lab"]},{"year":2024,"claim":"Showed a stromal role in cancer-associated adipocytes where TGF-β-driven FAM3C suppresses adipocyte-mesenchymal transition while supporting tumor growth.","evidence":"TGF-β neutralization, adipocyte co-culture, FAM3C knockdown in CAAs, GEMM tumor growth","pmids":["38117489"],"confidence":"Medium","gaps":["Receptor/signaling in adipocytes not defined","Apparent context-dependent EMT outcomes not reconciled"]},{"year":2026,"claim":"Defined Golgi retention of FAM3C via signal-peptide anchoring and its impact on Golgi morphology, secretion, and TNBC invasiveness.","evidence":"Subcellular fractionation, live-cell imaging, signal peptide mutagenesis, secretion and invasion assays","pmids":["41247074"],"confidence":"Medium","gaps":["Mechanism of Golgi-based effect on secretion unclear","Relationship between retained and secreted pools unresolved"]},{"year":2026,"claim":"Identified a USP33-eEF1A1 axis that boosts ILEI protein synthesis to drive EMT and lenvatinib resistance in hepatocellular carcinoma.","evidence":"CRISPR KO screen, transcriptome/proteomics, deubiquitinase assays, eEF1A1 stability Western blot","pmids":["42144151"],"confidence":"Medium","gaps":["Direct vs indirect effect of eEF1A1 on ILEI translation unclear","Single lab"]},{"year":null,"claim":"How a single secreted protein reconciles its multiple receptor systems (LIFR, RalA via EVs), its intracellular Golgi and γ-secretase functions, and its opposing context-dependent EMT/metabolic roles into a unified mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking dimer state, receptor engagement, and intracellular functions","Tissue determinants of secreted vs retained FAM3C unknown","Structural basis of receptor recognition undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[9,10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,11,9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[25]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[21,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,19,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,23]}],"complexes":[],"partners":["LIFR","RALA","UBE4A","PSEN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92520","full_name":"Protein FAM3C","aliases":["Interleukin-like EMT inducer"],"length_aa":227,"mass_kda":24.7,"function":"May be involved in retinal laminar formation. Promotes epithelial to mesenchymal transition","subcellular_location":"Secreted; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q92520/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM3C","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FAM3C","total_profiled":1310},"omim":[{"mim_id":"608618","title":"FAMILY WITH SEQUENCE SIMILARITY 3, MEMBER C; FAM3C","url":"https://www.omim.org/entry/608618"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM3C"},"hgnc":{"alias_symbol":["GS3876","ILEI"],"prev_symbol":[]},"alphafold":{"accession":"Q92520","domains":[{"cath_id":"-","chopping":"56-222","consensus_level":"high","plddt":98.0963,"start":56,"end":222},{"cath_id":"1.20.5","chopping":"1-52","consensus_level":"medium","plddt":71.9448,"start":1,"end":52}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92520","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92520-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92520-F1-predicted_aligned_error_v6.png","plddt_mean":91.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM3C","jax_strain_url":"https://www.jax.org/strain/search?query=FAM3C"},"sequence":{"accession":"Q92520","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92520.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92520/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92520"}},"corpus_meta":[{"pmid":"20154680","id":"PMC_20154680","title":"TGF-beta-mediated 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disorders","date":"2024-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.21.624658","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25549,"output_tokens":7502,"usd":0.094589,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16974,"output_tokens":7067,"usd":0.130773,"stage2_stop_reason":"end_turn"},"total_usd":0.225362,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"hnRNP E1 (encoded by PCBP1) binds a 33-nucleotide TGF-β-activated translation (BAT) element in the 3' UTR of ILEI mRNA and represses its translation. TGF-β signaling leads to phosphorylation of hnRNP E1 at Ser43 by PKBβ/Akt2, causing its release from the BAT element and translational de-repression of ILEI.\",\n      \"method\": \"RNA pulldown, site-directed mutagenesis of BAT element, phospho-specific antibodies, RNAi knockdown with translational reporter assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding assay, mutagenesis, kinase identification, functional EMT readout), replicated in lung cancer context (PMID:24072492)\",\n      \"pmids\": [\"20154680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Stable overexpression of ILEI in mouse mammary epithelial cells (EpH4 and EpRas) induces EMT, tumor growth, and metastasis independently of TGFβ-R signaling; RNAi-mediated knockdown prevents and reverts TGFβ-dependent EMT and abrogates metastasis formation.\",\n      \"method\": \"Stable overexpression, RNAi knockdown, in vivo tumor/metastasis assays, expression profiling\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with in vivo metastasis endpoints, replicated across multiple studies\",\n      \"pmids\": [\"16959614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ILEI cooperates with oncogenic Ras to cause TGF-β-independent EMT in hepatocytes; ILEI-induced PDGF/PDGF-R signaling is required for enhanced cell migration, nuclear accumulation of β-catenin, nuclear pY-Stat3, and accelerated lung metastasis growth, as shown by dominant-negative PDGF-R rescue experiments.\",\n      \"method\": \"Dominant-negative receptor expression, Western blotting for signaling intermediates, in vivo metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via dominant-negative receptor plus in vivo endpoint, single lab\",\n      \"pmids\": [\"19015638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of murine FAM3B PANDER reveals a globular β-β-α fold (two antiparallel β sheets lined by three short helices forming a water-filled cavity), inconsistent with the predicted four-helix bundle cytokine fold; the fold is conserved throughout the FAM3 superfamily including FAM3C/ILEI, indicating FAM3 proteins represent a distinct structural class of signaling molecules.\",\n      \"method\": \"X-ray crystallography (crystal structure of FAM3B PANDER as FAM3 family representative)\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional inference extended to FAM3C by fold conservation; later confirmed by direct FAM3C crystal structure (PMID:28751379)\",\n      \"pmids\": [\"23333428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ILEI binds to the γ-secretase complex (specifically its presenilin subunit) and destabilizes the β-secretase-cleaved APP C-terminal fragment (the penultimate Aβ precursor), thereby reducing Aβ production without affecting Notch signaling or γ-secretase catalytic activity; TGF-β signaling induces neuronal ILEI expression; transgenic ILEI overexpression reduces brain Aβ burden and ameliorates memory deficits in AD model mice.\",\n      \"method\": \"Co-immunoprecipitation with γ-secretase complex, APP-CTF stability assays, transgenic mouse model, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing complex, biochemical substrate (APP-CTF) destabilization assay, in vivo transgenic rescue with functional (cognitive) endpoint\",\n      \"pmids\": [\"24894631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The ubiquitin ligase UBE4A directly interacts with ILEI protein and mediates its polyubiquitination and proteasomal degradation. Mass spectrometry of FLAG-ILEI immunoprecipitates identified UBE4A and UBE3C as interactors; overexpression of UBE4A (but not UBE3C) destabilized ILEI; RNAi knockdown of UBE4A caused accumulation of ILEI; co-IP confirmed endogenous ILEI–UBE4A interaction.\",\n      \"method\": \"Mass spectrometry of immunoprecipitates, co-immunoprecipitation, proteasome inhibitor treatment (MG-132), RNAi, overexpression of ubiquitin ligases\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS identification plus reciprocal co-IP plus functional ubiquitination assay with mutagenic specificity (UBE4A vs UBE3C), single lab\",\n      \"pmids\": [\"27862841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAM3C overexpression in hepatocytes upregulates HSF1 expression, which elevates calmodulin (CaM) protein by inducing CALM1 transcription, activating Akt in a Ca²⁺- and insulin-independent manner; this FAM3C-HSF1-CaM-Akt pathway suppresses gluconeogenesis via nuclear exclusion of FOXO1 and reduces lipid deposition.\",\n      \"method\": \"Adenoviral overexpression in hepatocytes and mouse liver, Western blotting, promoter/transcription assays, CaM-dependent pathway inhibition\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo overexpression with defined pathway intermediates, single lab, pathway rescue not shown\",\n      \"pmids\": [\"28246289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fam3c is expressed during osteoblast differentiation and overexpression reduces Runx2 expression at both mRNA and protein levels, inhibiting alkaline phosphatase activity; knockdown has the opposite effect. Fam3c is localized intracellularly in the cytoplasm during osteoblast differentiation and is not secreted, suggesting intracellular function in this context. Fam3c and TGF-β1 reciprocally regulate each other.\",\n      \"method\": \"siRNA knockdown, overexpression, RT-PCR, Western blot, immunofluorescence localization, alkaline phosphatase activity assay\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined molecular target (Runx2), direct localization experiment, single lab\",\n      \"pmids\": [\"27914282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fam3c knockout mice show decreased trabecular bone number in tibiae and increased cortical bone mineral density; knockout bone marrow cells display accelerated osteogenic differentiation and mineralization in vitro, establishing a functional role for Fam3c in osteoblast differentiation and bone homeostasis.\",\n      \"method\": \"Knockout mouse generation, micro-CT analysis, in vitro osteogenic differentiation of bone marrow stromal cells\",\n      \"journal\": \"BoneKEy reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined bone phenotype and in vitro cellular readout, single lab\",\n      \"pmids\": [\"27087939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of FAM3C/ILEI reveal a β-β-α fold inconsistent with interleukin classification; ILEI exists as monomers and covalent domain-swapped dimers formed by intramolecular-to-intermolecular disulfide isomerization at Cys185. Dimeric but not monomeric ILEI causes dose-dependent increase in EpRas cell invasiveness comparable to TGF-β.\",\n      \"method\": \"X-ray crystallography, analytical ultracentrifugation, disulfide bond analysis, cell invasion assay with purified monomers vs. dimers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biochemical dimer/monomer separation plus functional cell invasion assay directly linking dimerization to activity\",\n      \"pmids\": [\"28751379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Covalent dimerization of ILEI via Cys185 is essential for EMT induction, tumor growth, and lung metastasis in vivo. Mutation C185A prevents dimerization without affecting secretion; C185A-expressing tumor cells fail to induce EMT or form large tumors/metastases in nude mice, whereas wild-type ILEI-expressing cells do. ILEI monomers and C185A mutants affect only cell motility, not full EMT.\",\n      \"method\": \"Cysteine mutagenesis (C185A), pulse-chase experiments, purified protein incubation with serum, in vivo xenograft/metastasis assays, scratch assay and time-lapse microscopy\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with biochemical dimerization assay plus in vivo tumor/metastasis functional endpoint, corroborates parallel structural study (PMID:28751379)\",\n      \"pmids\": [\"28837266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAM3C functions as a secreted hepatokine; conditioned medium from FAM3C-overexpressing hepatocytes induces Akt phosphorylation in recipient cells, and this is blocked by anti-FAM3C antibodies. Recombinant FAM3C protein activates Akt in a HSF1- and CaM-dependent manner, represses FOXO1 nuclear activity and gluconeogenesis independently of insulin in type 1 diabetic mice.\",\n      \"method\": \"Conditioned medium transfer, anti-FAM3C antibody neutralization, recombinant protein treatment, hepatocyte culture with signaling readouts, in vivo STZ-diabetic mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody neutralization confirms secreted function, recombinant protein with defined pathway readouts, single lab\",\n      \"pmids\": [\"29285313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ILEI is transcriptionally up-regulated by USF-1 (an E-box-binding bHLH transcription factor) through direct binding of USF-1 to the ILEI promoter. UV-mediated USF-1 activation increases ILEI expression; shRNA knockdown of USF-1 decreases ILEI transcription and tumor cell migration. shRNA knockdown of ILEI in melanoma attenuates lung colonization but not primary tumor formation.\",\n      \"method\": \"shRNA knockdown, promoter reporter assay, chromatin immunoprecipitation (direct USF-1–promoter interaction), in vivo lung colonization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes direct promoter binding, functional shRNA with in vivo endpoint, single lab\",\n      \"pmids\": [\"29871931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ILEI signals through LIFR (leukemia inhibitory factor receptor) as its receptor; FAM3C/LIFR interaction in the extracellular space activates STAT3 signaling to drive EMT and breast cancer stem cell (BCSC) formation. Reduction of either ILEI or LIFR reduces tumor growth, tumor-initiating cells, and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (ILEI–LIFR interaction), RNAi knockdown of ILEI and LIFR, in vivo orthotopic tumor assays, STAT3 phosphorylation readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying receptor, loss-of-function for both ligand and receptor with in vivo tumor/metastasis endpoints, replicated in renal fibrosis context (PMID:35093095)\",\n      \"pmids\": [\"30692635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM3C activates a YY1–HSF1 signaling axis to promote proliferation and migration of breast cancer cells; YY1 directly activates HSF1 transcription; FAM3C inhibition represses TGF-β-induced HSF1 activation and downstream HSF1-Akt-Cyclin D1 pathway activity. YY1 and HSF1 had little effect on FAM3C expression itself.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blotting, promoter reporter assay for HSF1 by YY1, TGF-β stimulation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay for YY1→HSF1 direct activation, epistatic ordering via sequential knockdown, single lab\",\n      \"pmids\": [\"30887707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Transcriptional downregulation of FAM3C in the Alzheimer's brain is mediated by reduced nuclear levels and impaired genomic DNA binding of SP1 and EBF1. Basal FAM3C promoter activity requires SP1 and EBF1; SMAD1 is an inducible transcriptional activator and KLF6 is a transcriptional repressor of FAM3C. Genomic deletion of the basal promoter sequence in HEK293 and Neuro-2a cells markedly reduced FAM3C expression.\",\n      \"method\": \"Promoter deletion/reporter assays, CRISPR genomic deletion, promoter DNA-binding assays with nuclear extracts from AD and control brains, expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR promoter deletion plus direct DNA-binding assay with disease-relevant nuclear extracts, single lab\",\n      \"pmids\": [\"34378027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM3C/ILEI is co-amplified with MET on chromosome 7q31; ILEI knockdown impairs both c-MET-independent and c-MET-dependent cancer cell invasion but does not affect proliferation; c-MET inhibition reduces ILEI secretion; ILEI knockdown prevents c-MET-signaling-induced elevated MMP-2 and MMP-9 expression and secretion; combined ILEI knockdown plus c-MET inhibition reduces invasive tumor xenograft growth.\",\n      \"method\": \"Copy number analysis, shRNA knockdown, MMP ELISA/Western blot, invasion assay, in vivo xenograft tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway placement of ILEI downstream of c-MET for MMP regulation plus in vivo endpoint, single lab\",\n      \"pmids\": [\"33596971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Extracellular release of ILEI and Aβ is dependent on neuronal activation via tetanus toxin-sensitive synaptic vesicle exocytosis; ILEI and Aβ are released from distinct synapse subpopulations; AMPA-receptor activation causes opposing changes in extracellular ILEI and Aβ levels; spontaneous ILEI and Aβ fluctuations are inversely correlated, supporting ILEI as a negative regulator of Aβ production in specific synapse types.\",\n      \"method\": \"In vivo microdialysis in APP-knockin mice, ILEI-specific ELISA, selective synaptic receptor pharmacology, tetanus toxin treatment\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo microdialysis with pharmacological manipulation of distinct synaptic receptor subsets, single lab\",\n      \"pmids\": [\"33492290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human FAM3C can substitute for the Fam3L2 domain of C. elegans FAMP-1 in AFD neurons to rescue memory-based thermotaxis behavior in famp-1 mutants; in vitro assays show that FAM3C (like the Fam3L2 domain) can bind carbohydrates similarly to the stem domain of POMGnT1, suggesting a carbohydrate-binding activity.\",\n      \"method\": \"In vivo rescue of C. elegans thermotaxis (neuron-specific expression), in vitro carbohydrate-binding assay\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue in an orthologous system plus in vitro carbohydrate binding assay, single lab\",\n      \"pmids\": [\"36712359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ILEI promotes renal tubular EMT by binding and activating LIFR (co-immunoprecipitation in HK2 cells), with downstream phosphorylation of Akt and ERK; ILEI knockdown in the UUO mouse model of renal fibrosis reduced EMT markers and fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (ILEI–LIFR), Western blotting for pAkt/pERK, shRNA knockdown in UUO mouse model, in vitro transwell/WB assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirms ILEI–LIFR interaction with defined downstream signaling, in vivo UUO model, single lab; consistent with PMID:30692635\",\n      \"pmids\": [\"35093095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TGF-β1 from tumor cells induces neutrophils to produce FAM3C via Smad2/3 signaling; FAM3C then promotes tumor cell EMT through JNK-ZEB1/Snail signaling; enhanced neutrophil–tumor cell crosstalk also requires integrin α6β1/α6β4 interaction with CD151.\",\n      \"method\": \"Co-culture experiments, Smad2/3 pathway inhibition, JNK inhibition, Western blotting for ZEB1/Snail, in vivo tumor-bearing mouse model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined paracrine signaling pathway with pharmacological pathway inhibition and in vivo model, single lab\",\n      \"pmids\": [\"37056931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM3C drives a novel oncogenic signaling mode via extracellular vesicles (EVs): FAM3C in tumor-derived EVs is taken up by recipient cells and activates oncogenic signaling through a novel interaction with the Ras-related protein RalA, triggering downstream Src/STAT3 cascade activation, phenocopying endogenous FAM3C overexpression.\",\n      \"method\": \"EV proteomic mass spectrometry, co-immunoprecipitation (FAM3C–RalA), EV transfer to recipient cells, Src/STAT3 signaling readouts, in vivo metastasis assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP plus functional EV transfer assay with defined signaling readout, single lab\",\n      \"pmids\": [\"36632230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 (hnRNP E1) upregulates LIFR transcription at the LIFR promoter; FAM3C participates in transcriptional regulation of LIFR; downstream TWIST1 transcription factor maintains LIFR expression; FAM3C/LIFR/STAT3 signaling forms a feed-forward loop promoting BCSC invasion, migration, and self-renewal.\",\n      \"method\": \"Promoter reporter assay, PCBP1 knockdown, bioinformatic transcriptomic analysis, cell invasion/migration assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay plus functional BCSC assays, single lab; extends PMID:30692635\",\n      \"pmids\": [\"37927213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ILEI overexpression in keratinocytes triggers ERK and Akt signaling, which activates STAT3 via Ser727 phosphorylation, driving psoriasiform hyperproliferation, impaired epidermal differentiation, and neutrophil recruitment. Keratinocyte-specific ILEI deletion ameliorates TPA-induced skin inflammation. Pharmacological inhibition of urokinase reduces ILEI secretion and psoriasiform symptoms.\",\n      \"method\": \"Inducible keratinocyte-specific ILEI transgenic mice (K5-ILEIind), keratinocyte-specific knockout, TPA challenge, Western blotting for pERK/pAkt/pSTAT3, urokinase inhibitor treatment\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal transgenic overexpression and tissue-specific KO with defined signaling mechanism, in vivo phenotype, and pharmacological rescue, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37226685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM3C expression in cancer-associated adipocytes (CAAs) is driven by TGF-β signaling from breast cancer cells; FAM3C in CAAs suppresses adipocyte-mesenchymal transition and fibrosis within the TME; FAM3C knockdown in CAAs inhibits primary and metastatic tumor growth in a genetically engineered mouse model.\",\n      \"method\": \"TGF-β neutralizing antibody treatment, adipocyte co-culture, FAM3C knockdown in CAAs, genetically engineered mouse model of breast cancer, tumor growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody neutralization establishes TGF-β as upstream driver, in vivo GEMM with tissue-specific knockdown, single lab\",\n      \"pmids\": [\"38117489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM3C is retained in the Golgi apparatus through anchoring of its signal peptide into the membrane before the signal peptide and pro-peptide are processed and removed; while Golgi-retained, FAM3C alters Golgi morphology and affects protein secretion and invasive potential of TNBC cells.\",\n      \"method\": \"Subcellular fractionation, live-cell imaging, signal peptide mutagenesis, Golgi morphology assay, secretion and invasion assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (altered secretion and invasion), single lab, peer-reviewed\",\n      \"pmids\": [\"41247074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP33 acts as a deubiquitinase for eEF1A1, stabilizing eEF1A1 protein and thereby promoting ILEI protein synthesis; this USP33/eEF1A1/ILEI axis drives EMT and lenvatinib resistance in hepatocellular carcinoma.\",\n      \"method\": \"CRISPR KO screen, transcriptome sequencing, proteomic analysis, deubiquitinase activity assays, Western blotting for eEF1A1 stability\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen followed by proteomic identification plus deubiquitinase functional assay placing eEF1A1 upstream of ILEI translation, single lab\",\n      \"pmids\": [\"42144151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FAM3C/XFAM3C is involved in retinal laminar formation in Xenopus: overexpression causes retinal laminar disorganization and increased eye size; morpholino-mediated loss-of-function causes photoreceptor cell dislocation without affecting cellular differentiation.\",\n      \"method\": \"Xenopus gain-of-function overexpression and morpholino antisense loss-of-function, retinal histology\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function in Xenopus with defined tissue-level phenotype, single lab\",\n      \"pmids\": [\"20059962\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM3C/ILEI is a secreted cytokine-like protein with a β-β-α fold (not a four-helix bundle) that exists as monomers and covalent domain-swapped dimers (via Cys185); the dimer is the active species for EMT induction and metastasis. Its translation is repressed by hnRNP E1/PCBP1 binding a BAT element in its 3' UTR, and is de-repressed when TGF-β signaling triggers Akt2-mediated phosphorylation of hnRNP E1 at Ser43. Once secreted, ILEI signals through LIFR to activate STAT3 (driving EMT and breast cancer stem cell formation), and through RalA to activate Src/STAT3 when delivered via extracellular vesicles; it also activates ERK/Akt pathways in multiple contexts. Intracellularly, FAM3C is retained in the Golgi via its signal peptide, where it modulates Golgi morphology and protein secretion. Its protein stability is regulated post-translationally by the ubiquitin ligase UBE4A (mediating proteasomal degradation) and by the deubiquitinase USP33 acting via eEF1A1 to enhance ILEI synthesis. In neurons, ILEI binds the γ-secretase complex and destabilizes the APP C-terminal fragment to suppress Aβ production without inhibiting γ-secretase activity, and is released from synaptic vesicles in an activity-dependent manner. FAM3C also functions as a hepatokine activating an HSF1-CaM-Akt axis to suppress gluconeogenesis, and regulates osteoblast differentiation by suppressing Runx2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM3C/ILEI is a secreted signaling protein with a distinct β-β-α fold that drives epithelial-to-mesenchymal transition (EMT), tumor growth, and metastasis [#1, #9]. Structurally it belongs to a distinct class of FAM3 superfamily molecules rather than the four-helix-bundle cytokines [#3, #9], and it exists as monomers and covalent domain-swapped dimers formed via disulfide isomerization at Cys185; the dimer is the active species, and the C185A mutant retains secretion but fails to induce EMT, tumor growth, or metastasis in vivo [#9, #10]. ILEI signals extracellularly through the receptor LIFR to activate STAT3, driving EMT and breast cancer stem cell formation, and the same ILEI/LIFR/STAT3 axis operates in renal tubular EMT and fibrosis [#13, #19]; it also activates ERK/Akt cascades in multiple contexts, including keratinocyte hyperproliferation in psoriasiform inflammation [#19, #23]. When delivered in extracellular vesicles, FAM3C engages RalA to trigger Src/STAT3 signaling [#21]. Its output is tightly controlled at multiple levels: TGF-β signaling de-represses ILEI translation by driving Akt2-mediated phosphorylation of hnRNP E1/PCBP1 (Ser43), releasing it from a BAT element in the 3' UTR [#0]; transcription is governed by USF-1, SP1/EBF1, SMAD1, and KLF6 [#12, #15]; and protein levels are set post-translationally by UBE4A-mediated proteasomal degradation and by a USP33–eEF1A1 axis that promotes ILEI synthesis [#5, #26]. Beyond cancer, FAM3C is multifunctional: in neurons it binds the γ-secretase complex (presenilin) and destabilizes the APP C-terminal fragment to suppress Aβ production without inhibiting catalysis, and is released in an activity-dependent manner from synaptic vesicles [#4, #17]; as a hepatokine it activates an HSF1–calmodulin–Akt axis that excludes FOXO1 from the nucleus to suppress gluconeogenesis [#6, #11]; and it regulates osteoblast differentiation by suppressing Runx2 and bone homeostasis in knockout mice [#7, #8]. Intracellularly, FAM3C is retained in the Golgi via its signal peptide, where it modulates Golgi morphology and protein secretion [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that ILEI is a causal driver of EMT and metastasis rather than a bystander marker, by demonstrating reciprocal gain- and loss-of-function effects independent of TGF-β receptor signaling.\",\n      \"evidence\": \"Stable overexpression and RNAi knockdown in mouse mammary epithelial cells with in vivo tumor/metastasis endpoints\",\n      \"pmids\": [\"16959614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and downstream signaling not yet identified\", \"Molecular form of active ILEI unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed ILEI upstream of PDGF/PDGF-R signaling in driving TGF-β-independent EMT, linking it to β-catenin and Stat3 nuclear accumulation.\",\n      \"evidence\": \"Dominant-negative PDGF-R rescue in Ras-transformed hepatocytes with in vivo metastasis assays\",\n      \"pmids\": [\"19015638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ILEI receptor not defined\", \"PDGF-R activation mechanism by ILEI unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Solved how TGF-β controls ILEI output post-transcriptionally, identifying a translational switch governed by hnRNP E1 phosphorylation.\",\n      \"evidence\": \"RNA pulldown, BAT element mutagenesis, phospho-specific antibodies and translational reporters\",\n      \"pmids\": [\"20154680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address transcriptional regulation\", \"Kinetics relative to secretion not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended FAM3C function to vertebrate development, implicating it in retinal lamination.\",\n      \"evidence\": \"Xenopus overexpression and morpholino loss-of-function with retinal histology\",\n      \"pmids\": [\"20059962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism in retina unknown\", \"No receptor or signaling pathway defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reclassified the FAM3 superfamily structurally, showing a β-β-α fold rather than the predicted cytokine fold, redefining ILEI as a distinct class of signaling molecule.\",\n      \"evidence\": \"X-ray crystallography of FAM3B PANDER with fold conservation inferred for FAM3C\",\n      \"pmids\": [\"23333428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FAM3C structure not yet solved\", \"Functional consequence of the fold not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a non-oncogenic neuronal role, showing ILEI binds γ-secretase and destabilizes APP-CTF to suppress Aβ without blocking catalysis.\",\n      \"evidence\": \"Reciprocal co-IP, APP-CTF stability assays, transgenic AD mouse rescue with cognitive endpoints\",\n      \"pmids\": [\"24894631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CTF destabilization unclear\", \"Relationship to secreted/EMT functions not connected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified UBE4A as a direct E3 ligase controlling ILEI protein stability via proteasomal degradation.\",\n      \"evidence\": \"MS of immunoprecipitates, reciprocal co-IP, MG-132, ubiquitin ligase overexpression and RNAi\",\n      \"pmids\": [\"27862841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites not mapped\", \"Physiological contexts regulating UBE4A activity unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined FAM3C as a hepatic regulator of glucose metabolism via an HSF1-CaM-Akt axis suppressing gluconeogenesis.\",\n      \"evidence\": \"Adenoviral overexpression in hepatocytes and mouse liver with transcription/pathway readouts\",\n      \"pmids\": [\"28246289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating hepatic FAM3C signaling not defined\", \"Pathway rescue not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established FAM3C as a regulator of osteoblast differentiation acting through suppression of Runx2, with a non-secreted intracellular localization in this context.\",\n      \"evidence\": \"Reciprocal knockdown/overexpression, immunofluorescence localization, alkaline phosphatase assays\",\n      \"pmids\": [\"27914282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking FAM3C to Runx2 unknown\", \"Reconciliation of secreted vs intracellular roles unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed an in vivo role in bone homeostasis, showing Fam3c knockout alters trabecular and cortical bone and accelerates osteogenic differentiation.\",\n      \"evidence\": \"Knockout mice, micro-CT, in vitro osteogenic differentiation of marrow stromal cells\",\n      \"pmids\": [\"27087939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous vs systemic contributions not separated\", \"Molecular pathway in vivo not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Directly determined the FAM3C structure and identified covalent domain-swapped dimerization at Cys185 as the active species for invasion.\",\n      \"evidence\": \"X-ray crystallography, analytical ultracentrifugation, disulfide analysis, monomer vs dimer invasion assays\",\n      \"pmids\": [\"28751379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for dimerization in vivo unclear\", \"Receptor recognition of dimer not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that Cys185 dimerization is essential for full EMT and metastasis in vivo, separating dimer-driven EMT from monomer-driven motility.\",\n      \"evidence\": \"C185A mutagenesis, pulse-chase, in vivo xenograft/metastasis assays, motility imaging\",\n      \"pmids\": [\"28837266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why monomers retain only motility activity unexplained\", \"Dimer-specific signaling not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed FAM3C acts as a bona fide secreted hepatokine by antibody neutralization and recombinant protein activity on Akt and gluconeogenesis.\",\n      \"evidence\": \"Conditioned medium transfer, anti-FAM3C neutralization, recombinant protein, STZ-diabetic mice\",\n      \"pmids\": [\"29285313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor for hepatokine signaling unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified USF-1 as a direct transcriptional activator of ILEI linking stress (UV) to ILEI-driven tumor cell migration and colonization.\",\n      \"evidence\": \"ChIP, promoter reporter, shRNA knockdown, in vivo lung colonization\",\n      \"pmids\": [\"29871931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay with translational control not addressed\", \"Other promoter inputs not yet defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified LIFR as the receptor for ILEI, linking it to STAT3 activation, EMT, and breast cancer stem cell formation.\",\n      \"evidence\": \"Reciprocal co-IP, RNAi of ligand and receptor, orthotopic tumor assays, STAT3 readout\",\n      \"pmids\": [\"30692635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dimer-receptor interaction not resolved\", \"Co-receptor requirements unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a YY1-HSF1-Akt-Cyclin D1 axis downstream of TGF-β and FAM3C promoting breast cancer proliferation and migration.\",\n      \"evidence\": \"Sequential knockdown/overexpression, promoter reporter for YY1→HSF1, TGF-β stimulation\",\n      \"pmids\": [\"30887707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role of FAM3C in this axis unclear\", \"Connection to LIFR/STAT3 not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the transcriptional circuit controlling basal and disease-altered FAM3C expression in the brain (SP1/EBF1 basal, SMAD1 inducer, KLF6 repressor).\",\n      \"evidence\": \"Promoter deletion/reporter, CRISPR genomic deletion, DNA-binding assays with AD brain nuclear extracts\",\n      \"pmids\": [\"34378027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link of reduced FAM3C to AD pathology not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed activity-dependent synaptic release of ILEI and inverse coupling with Aβ, supporting ILEI as a negative regulator of Aβ in specific synapses.\",\n      \"evidence\": \"In vivo microdialysis in APP-knockin mice, ILEI ELISA, synaptic receptor pharmacology, tetanus toxin\",\n      \"pmids\": [\"33492290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of synapse-subtype specificity unknown\", \"Mechanism connecting release to CTF destabilization unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned ILEI downstream of c-MET for MMP-2/9-driven invasion and showed it is co-amplified with MET, identifying a co-targetable axis.\",\n      \"evidence\": \"Copy number analysis, shRNA, MMP assays, invasion and in vivo xenograft assays\",\n      \"pmids\": [\"33596971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect MET-ILEI relationship unresolved\", \"Mechanism of MET-dependent ILEI secretion unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the ILEI/LIFR/Akt/ERK axis beyond cancer to renal tubular EMT and fibrosis.\",\n      \"evidence\": \"Co-IP in HK2 cells, pAkt/pERK Western blot, shRNA in UUO mouse model\",\n      \"pmids\": [\"35093095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor stoichiometry unaddressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided cross-species evidence for a conserved FAM3C carbohydrate-binding activity by rescuing C. elegans neuronal behavior.\",\n      \"evidence\": \"C. elegans thermotaxis rescue with neuron-specific expression, in vitro carbohydrate-binding assay\",\n      \"pmids\": [\"36712359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological carbohydrate ligand in mammals unknown\", \"Relevance to secreted signaling unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered an extracellular-vesicle-mediated signaling mode in which FAM3C engages RalA to drive Src/STAT3 oncogenic signaling.\",\n      \"evidence\": \"EV proteomics, FAM3C-RalA co-IP, EV transfer, Src/STAT3 readouts, in vivo metastasis\",\n      \"pmids\": [\"36632230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How extracellular FAM3C accesses intracellular RalA unresolved\", \"Relationship to LIFR pathway unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a paracrine route in which tumor-derived TGF-β induces neutrophil FAM3C that promotes tumor EMT via JNK-ZEB1/Snail.\",\n      \"evidence\": \"Co-culture, Smad2/3 and JNK inhibition, ZEB1/Snail Western blot, in vivo tumor model\",\n      \"pmids\": [\"37056931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating neutrophil-derived FAM3C signaling not defined\", \"Integrin-CD151 contribution mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a non-cancer inflammatory role, with ILEI driving psoriasiform keratinocyte hyperproliferation via ERK/Akt-STAT3(Ser727).\",\n      \"evidence\": \"Inducible keratinocyte transgenic and knockout mice, TPA challenge, pERK/pAkt/pSTAT3 Western, urokinase inhibition\",\n      \"pmids\": [\"37226685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor in keratinocytes not defined\", \"Role of dimerization in this context not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added a feed-forward transcriptional loop in which PCBP1 and FAM3C upregulate LIFR with TWIST1 maintenance, reinforcing BCSC properties.\",\n      \"evidence\": \"Promoter reporter, PCBP1 knockdown, transcriptomic analysis, invasion/migration assays\",\n      \"pmids\": [\"37927213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FAM3C influences LIFR transcription unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed a stromal role in cancer-associated adipocytes where TGF-β-driven FAM3C suppresses adipocyte-mesenchymal transition while supporting tumor growth.\",\n      \"evidence\": \"TGF-β neutralization, adipocyte co-culture, FAM3C knockdown in CAAs, GEMM tumor growth\",\n      \"pmids\": [\"38117489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signaling in adipocytes not defined\", \"Apparent context-dependent EMT outcomes not reconciled\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined Golgi retention of FAM3C via signal-peptide anchoring and its impact on Golgi morphology, secretion, and TNBC invasiveness.\",\n      \"evidence\": \"Subcellular fractionation, live-cell imaging, signal peptide mutagenesis, secretion and invasion assays\",\n      \"pmids\": [\"41247074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Golgi-based effect on secretion unclear\", \"Relationship between retained and secreted pools unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a USP33-eEF1A1 axis that boosts ILEI protein synthesis to drive EMT and lenvatinib resistance in hepatocellular carcinoma.\",\n      \"evidence\": \"CRISPR KO screen, transcriptome/proteomics, deubiquitinase assays, eEF1A1 stability Western blot\",\n      \"pmids\": [\"42144151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect of eEF1A1 on ILEI translation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted protein reconciles its multiple receptor systems (LIFR, RalA via EVs), its intracellular Golgi and γ-secretase functions, and its opposing context-dependent EMT/metabolic roles into a unified mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking dimer state, receptor engagement, and intracellular functions\", \"Tissue determinants of secreted vs retained FAM3C unknown\", \"Structural basis of receptor recognition undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [9, 10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 11, 9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 19, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LIFR\", \"RalA\", \"UBE4A\", \"PSEN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}