Affinage

FAM3C

Protein FAM3C · UniProt Q92520

Length
227 aa
Mass
24.7 kDa
Annotated
2026-06-09
45 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2006 High

    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

    PMID:16959614

    Open questions at the time
    • Receptor and downstream signaling not yet identified
    • Molecular form of active ILEI unknown
  2. 2008 Medium

    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

    PMID:19015638

    Open questions at the time
    • Direct ILEI receptor not defined
    • PDGF-R activation mechanism by ILEI unclear
  3. 2010 High

    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

    PMID:20154680

    Open questions at the time
    • Does not address transcriptional regulation
    • Kinetics relative to secretion not resolved
  4. 2010 Medium

    Extended FAM3C function to vertebrate development, implicating it in retinal lamination.

    Evidence Xenopus overexpression and morpholino loss-of-function with retinal histology

    PMID:20059962

    Open questions at the time
    • Molecular mechanism in retina unknown
    • No receptor or signaling pathway defined
  5. 2013 High

    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

    PMID:23333428

    Open questions at the time
    • Direct FAM3C structure not yet solved
    • Functional consequence of the fold not addressed
  6. 2014 High

    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

    PMID:24894631

    Open questions at the time
    • Mechanism of CTF destabilization unclear
    • Relationship to secreted/EMT functions not connected
  7. 2016 High

    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

    PMID:27862841

    Open questions at the time
    • Ubiquitination sites not mapped
    • Physiological contexts regulating UBE4A activity unknown
  8. 2016 Medium

    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

    PMID:28246289

    Open questions at the time
    • Receptor mediating hepatic FAM3C signaling not defined
    • Pathway rescue not shown
  9. 2016 Medium

    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

    PMID:27914282

    Open questions at the time
    • Mechanism linking FAM3C to Runx2 unknown
    • Reconciliation of secreted vs intracellular roles unresolved
  10. 2016 Medium

    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

    PMID:27087939

    Open questions at the time
    • Cell-autonomous vs systemic contributions not separated
    • Molecular pathway in vivo not defined
  11. 2017 High

    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

    PMID:28751379

    Open questions at the time
    • Trigger for dimerization in vivo unclear
    • Receptor recognition of dimer not addressed
  12. 2017 High

    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

    PMID:28837266

    Open questions at the time
    • Why monomers retain only motility activity unexplained
    • Dimer-specific signaling not mapped
  13. 2017 Medium

    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

    PMID:29285313

    Open questions at the time
    • Receptor for hepatokine signaling unidentified
    • Single lab
  14. 2018 Medium

    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

    PMID:29871931

    Open questions at the time
    • Interplay with translational control not addressed
    • Other promoter inputs not yet defined
  15. 2019 High

    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

    PMID:30692635

    Open questions at the time
    • Stoichiometry and dimer-receptor interaction not resolved
    • Co-receptor requirements unknown
  16. 2019 Medium

    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

    PMID:30887707

    Open questions at the time
    • Direct vs indirect role of FAM3C in this axis unclear
    • Connection to LIFR/STAT3 not integrated
  17. 2021 Medium

    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

    PMID:34378027

    Open questions at the time
    • Causal link of reduced FAM3C to AD pathology not established
    • Single lab
  18. 2021 Medium

    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

    PMID:33492290

    Open questions at the time
    • Molecular basis of synapse-subtype specificity unknown
    • Mechanism connecting release to CTF destabilization unclear
  19. 2021 Medium

    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

    PMID:33596971

    Open questions at the time
    • Direct vs indirect MET-ILEI relationship unresolved
    • Mechanism of MET-dependent ILEI secretion unclear
  20. 2022 Medium

    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

    PMID:35093095

    Open questions at the time
    • Receptor stoichiometry unaddressed
    • Single lab
  21. 2022 Medium

    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

    PMID:36712359

    Open questions at the time
    • Physiological carbohydrate ligand in mammals unknown
    • Relevance to secreted signaling unclear
  22. 2023 Medium

    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

    PMID:36632230

    Open questions at the time
    • How extracellular FAM3C accesses intracellular RalA unresolved
    • Relationship to LIFR pathway unclear
  23. 2023 Medium

    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

    PMID:37056931

    Open questions at the time
    • Receptor mediating neutrophil-derived FAM3C signaling not defined
    • Integrin-CD151 contribution mechanistically unresolved
  24. 2023 High

    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

    PMID:37226685

    Open questions at the time
    • Receptor in keratinocytes not defined
    • Role of dimerization in this context not tested
  25. 2023 Medium

    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

    PMID:37927213

    Open questions at the time
    • Mechanism by which FAM3C influences LIFR transcription unclear
    • Single lab
  26. 2024 Medium

    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

    PMID:38117489

    Open questions at the time
    • Receptor/signaling in adipocytes not defined
    • Apparent context-dependent EMT outcomes not reconciled
  27. 2026 Medium

    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

    PMID:41247074

    Open questions at the time
    • Mechanism of Golgi-based effect on secretion unclear
    • Relationship between retained and secreted pools unresolved
  28. 2026 Medium

    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

    PMID:42144151

    Open questions at the time
    • Direct vs indirect effect of eEF1A1 on ILEI translation unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
LIFRPSEN1RALAUBE4A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. RNA pulldown, site-directed mutagenesis of BAT element, phospho-specific antibodies, RNAi knockdown with translational reporter assays Nature cell biology High 20154680
2006 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. Stable overexpression, RNAi knockdown, in vivo tumor/metastasis assays, expression profiling Cancer cell High 16959614
2008 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. Dominant-negative receptor expression, Western blotting for signaling intermediates, in vivo metastasis assays Oncogene Medium 19015638
2013 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. X-ray crystallography (crystal structure of FAM3B PANDER as FAM3 family representative) Structure High 23333428
2014 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. Co-immunoprecipitation with γ-secretase complex, APP-CTF stability assays, transgenic mouse model, behavioral testing Nature communications High 24894631
2016 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. Mass spectrometry of immunoprecipitates, co-immunoprecipitation, proteasome inhibitor treatment (MG-132), RNAi, overexpression of ubiquitin ligases IUBMB life High 27862841
2016 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. Adenoviral overexpression in hepatocytes and mouse liver, Western blotting, promoter/transcription assays, CaM-dependent pathway inhibition Diabetes Medium 28246289
2016 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. siRNA knockdown, overexpression, RT-PCR, Western blot, immunofluorescence localization, alkaline phosphatase activity assay Differentiation; research in biological diversity Medium 27914282
2016 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. Knockout mouse generation, micro-CT analysis, in vitro osteogenic differentiation of bone marrow stromal cells BoneKEy reports Medium 27087939
2017 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. X-ray crystallography, analytical ultracentrifugation, disulfide bond analysis, cell invasion assay with purified monomers vs. dimers The Journal of biological chemistry High 28751379
2017 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. Cysteine mutagenesis (C185A), pulse-chase experiments, purified protein incubation with serum, in vivo xenograft/metastasis assays, scratch assay and time-lapse microscopy The FEBS journal High 28837266
2017 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. Conditioned medium transfer, anti-FAM3C antibody neutralization, recombinant protein treatment, hepatocyte culture with signaling readouts, in vivo STZ-diabetic mouse model Oncotarget Medium 29285313
2018 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. shRNA knockdown, promoter reporter assay, chromatin immunoprecipitation (direct USF-1–promoter interaction), in vivo lung colonization assay The Journal of biological chemistry Medium 29871931
2019 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. Co-immunoprecipitation (ILEI–LIFR interaction), RNAi knockdown of ILEI and LIFR, in vivo orthotopic tumor assays, STAT3 phosphorylation readout Oncogene High 30692635
2019 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. siRNA knockdown, overexpression, Western blotting, promoter reporter assay for HSF1 by YY1, TGF-β stimulation Journal of cellular and molecular medicine Medium 30887707
2021 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. Promoter deletion/reporter assays, CRISPR genomic deletion, promoter DNA-binding assays with nuclear extracts from AD and control brains, expression analysis Human molecular genetics Medium 34378027
2021 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. Copy number analysis, shRNA knockdown, MMP ELISA/Western blot, invasion assay, in vivo xenograft tumor model Journal of experimental & clinical cancer research Medium 33596971
2021 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. In vivo microdialysis in APP-knockin mice, ILEI-specific ELISA, selective synaptic receptor pharmacology, tetanus toxin treatment Journal of Alzheimer's disease Medium 33492290
2022 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. In vivo rescue of C. elegans thermotaxis (neuron-specific expression), in vitro carbohydrate-binding assay PNAS nexus Medium 36712359
2022 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. Co-immunoprecipitation (ILEI–LIFR), Western blotting for pAkt/pERK, shRNA knockdown in UUO mouse model, in vitro transwell/WB assays Journal of translational medicine Medium 35093095
2023 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. Co-culture experiments, Smad2/3 pathway inhibition, JNK inhibition, Western blotting for ZEB1/Snail, in vivo tumor-bearing mouse model International journal of biological sciences Medium 37056931
2023 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. EV proteomic mass spectrometry, co-immunoprecipitation (FAM3C–RalA), EV transfer to recipient cells, Src/STAT3 signaling readouts, in vivo metastasis assay Theranostics Medium 36632230
2023 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. Promoter reporter assay, PCBP1 knockdown, bioinformatic transcriptomic analysis, cell invasion/migration assays Cancer biology & therapy Medium 37927213
2023 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. Inducible keratinocyte-specific ILEI transgenic mice (K5-ILEIind), keratinocyte-specific knockout, TPA challenge, Western blotting for pERK/pAkt/pSTAT3, urokinase inhibitor treatment EMBO molecular medicine High 37226685
2024 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. TGF-β neutralizing antibody treatment, adipocyte co-culture, FAM3C knockdown in CAAs, genetically engineered mouse model of breast cancer, tumor growth assay Cancer research Medium 38117489
2026 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. Subcellular fractionation, live-cell imaging, signal peptide mutagenesis, Golgi morphology assay, secretion and invasion assays Journal of molecular cell biology Medium 41247074
2026 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. CRISPR KO screen, transcriptome sequencing, proteomic analysis, deubiquitinase activity assays, Western blotting for eEF1A1 stability International journal of biological macromolecules Medium 42144151
2010 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. Xenopus gain-of-function overexpression and morpholino antisense loss-of-function, retinal histology Biochemical and biophysical research communications Medium 20059962

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nature cell biology 265 20154680
2006 ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer cell 154 16959614
2008 ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression. Oncogene 74 19015638
2019 TGFβ promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis. Oncogene 71 30692635
2019 FAM3C-YY1 axis is essential for TGFβ-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1. Journal of cellular and molecular medicine 50 30887707
2017 Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice. Diabetes 36 28246289
2014 The FAM3 superfamily member ILEI ameliorates Alzheimer's disease-like pathology by destabilizing the penultimate amyloid-β precursor. Nature communications 36 24894631
2013 ILEI drives epithelial to mesenchymal transition and metastatic progression in the lung cancer cell line A549. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 24072492
2023 Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. International journal of biological sciences 31 37056931
2004 Genomic organization and expression analysis of the murine Fam3c gene. Gene 24 15194199
2016 Neuronal expression of ILEI/FAM3C and its reduction in Alzheimer's disease. Neuroscience 23 27256505
2024 FAM3C in Cancer-Associated Adipocytes Promotes Breast Cancer Cell Survival and Metastasis. Cancer research 22 38117489
2021 Transcriptional downregulation of FAM3C/ILEI in the Alzheimer's brain. Human molecular genetics 22 34378027
2022 The ILEI/LIFR complex induces EMT via the Akt and ERK pathways in renal interstitial fibrosis. Journal of translational medicine 21 35093095
2021 FAM3C: an emerging biomarker and potential therapeutic target for cancer. Biomarkers in medicine 21 33666514
2016 Fam3c modulates osteogenic cell differentiation and affects bone volume and cortical bone mineral density. BoneKEy reports 21 27087939
2023 FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites. Theranostics 20 36632230
2018 Elevated FAM3C promotes cell epithelial- mesenchymal transition and cell migration in gastric cancer. OncoTargets and therapy 19 30584315
2016 The ubiquitin ligase UBE4A inhibits prostate cancer progression by targeting interleukin-like EMT inducer (ILEI). IUBMB life 19 27862841
2016 Fam3c modulates osteogenic differentiation by down-regulating Runx2. Differentiation; research in biological diversity 19 27914282
2013 FAM3B PANDER and FAM3C ILEI represent a distinct class of signaling molecules with a non-cytokine-like fold. Structure (London, England : 1993) 19 23333428
2010 Secreted factor FAM3C (ILEI) is involved in retinal laminar formation. Biochemical and biophysical research communications 18 20059962
2021 The FAM3C locus that encodes interleukin-like EMT inducer (ILEI) is frequently co-amplified in MET-amplified cancers and contributes to invasiveness. Journal of experimental & clinical cancer research : CR 16 33596971
2021 Significant effects of Ganoderma lucidum polysaccharide on lipid metabolism in diabetes may be associated with the activation of the FAM3C-HSF1-CAM signaling pathway. Experimental and therapeutic medicine 16 34131443
2019 miR-574-3p inhibits proliferation and invasion in esophageal cancer by targeting FAM3C and MAPK1. The Kaohsiung journal of medical sciences 16 31880039
2017 The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer. The Journal of biological chemistry 15 28751379
2017 Covalent dimerization of interleukin-like epithelial-to-mesenchymal transition (EMT) inducer (ILEI) facilitates EMT, invasion, and late aspects of metastasis. The FEBS journal 13 28837266
2018 ILEI is an important intermediate participating in the formation of TGF-β1-induced renal tubular EMT. Cell biochemistry and function 12 29336056
2017 FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice. Oncotarget 12 29285313
2018 Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1). The Journal of biological chemistry 11 29871931
2018 Overexpression of FAM3C protein as a novel biomarker for epithelial-mesenchymal transition and poor outcome in gastric cancer. International journal of clinical and experimental pathology 10 31949820
2023 PCBP1 regulates LIFR through FAM3C to maintain breast cancer stem cell self-renewal and invasiveness. Cancer biology & therapy 7 37927213
2023 FAM3C/ILEI protein is elevated in psoriatic lesions and triggers psoriasiform hyperproliferation in mice. EMBO molecular medicine 6 37226685
2021 Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations. Journal of Alzheimer's disease : JAD 6 33492290
2024 FAM3C Regulates Glioma Cell Proliferation, Invasion, Apoptosis, and Epithelial Mesenchymal Transition via the Notch Pathway. Cancer medicine 5 39629744
2012 Duplication of C7orf58, WNT16 and FAM3C in an obese female with a t(7;22)(q32.1;q11.2) chromosomal translocation and clinical features resembling Coffin-Siris Syndrome. PloS one 4 23300646
2024 H3K27ac-activated LncRNA NUTM2A-AS1 Facilitated the Progression of Colorectal Cancer Cells via MicroRNA-126-5p/FAM3C Axis. Current cancer drug targets 3 38347779
2024 Network-Based Transcriptome Analysis Reveals FAM3C as a Novel Potential Biomarker for Glioblastoma. Journal of cellular biochemistry 2 38923575
2023 Inducible overexpression of a FAM3C/ILEI transgene has pleiotropic effects with shortened life span, liver fibrosis and anemia in mice. PloS one 2 37713409
2022 Human FAM3C restores memory-based thermotaxis of Caenorhabditis elegans famp-1/m70.4 loss-of-function mutants. PNAS nexus 2 36712359
2022 Reclassification of Streptococcus ilei as a later heterotypic synonym of Streptococcus koreensis based on whole-genome sequence analysis. Archives of microbiology 1 35727397
2020 Genetic variants in the FAM3C gene are associated with lipid traits in Chinese children. Pediatric research 1 32316026
2026 Fam3C alters Golgi apparatus morphology and function in triple negative breast cancer. Journal of molecular cell biology 0 41247074
2026 USP33 contributes to EMT and Lenvatinib resistance by enhancing eEF1A1-mediated ILEI protein synthesis in hepatocellular carcinoma. International journal of biological macromolecules 0 42144151
2025 A novel IKZF1::FAM3C fusion associated with inversion of chromosome 7, inv(7)(p13q32), in relapsed acute myeloid leukemia. Journal of hematopathology 0 41269428

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