{"gene":"FNDC3B","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2012,"finding":"FNDC3B oncoprotein localizes to the Golgi network, and correct Golgi localization is essential for its transforming function. Overexpression induces EMT and activates PI3K/Akt, Rb1, and TGFβ signaling pathways. For TGFβ signaling, FNDC3B induces expression of all three TGFβ ligands and promotes TGFBR1 cell-surface localization.","method":"Cellular localization assays, RNAi knockdown, overexpression in mammary/kidney epithelial cells and hepatocytes, cancer pathway activation assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, RNAi, pathway analysis) in single lab; no structural or in vitro reconstitution","pmids":["22510613"],"is_preprint":false},{"year":2004,"finding":"Fad104 (FNDC3B) expression is rapidly induced in early adipogenesis and functions as a positive regulator of adipocyte differentiation; knockdown by RNAi represses adipogenesis in 3T3-L1 cells.","method":"RNAi knockdown, adipogenesis assays in 3T3-L1 cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (adipogenesis), replicated concept in subsequent studies","pmids":["15527760"],"is_preprint":false},{"year":2008,"finding":"Disruption of fad104 (FNDC3B) in mice causes rapid postnatal death, and fad104-deficient MEFs show reduced stress fiber formation, delayed cell adhesion, spreading, and migration, as well as inhibited adipocyte differentiation and cell proliferation.","method":"Gene targeting (knockout mice), mouse embryonic fibroblast analysis, cell adhesion assays, wound healing assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple orthogonal phenotypic readouts (proliferation, adhesion, spreading, migration) in primary cells","pmids":["19138685"],"is_preprint":false},{"year":2010,"finding":"Fad104 (FNDC3B) negatively regulates osteoblast differentiation: its expression decreases during osteogenesis, and fad104 deletion in MEFs facilitates osteoblast differentiation and elevates Runx2 levels. fad104 also suppresses BMP-2-mediated adipocyte differentiation.","method":"Gene knockout MEFs, osteoblast differentiation assays, western blot for Runx2","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined phenotype, single lab, multiple differentiation assays","pmids":["20493170"],"is_preprint":false},{"year":2011,"finding":"Fad104 (FNDC3B) is essential for lung maturation: fad104-deficient mice die due to lung dysplasia (atelectasis), FAD104 is strongly expressed in ATII cells in the developing lung, and its loss impairs ATII cell maturation and surfactant-associated protein expression.","method":"Knockout mouse phenotypic analysis, immunohistochemistry, surfactant protein expression assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with specific cellular and molecular phenotype (ATII cell maturation, surfactant proteins), replicated in same knockout model","pmids":["21704616"],"is_preprint":false},{"year":2013,"finding":"FAD104 (FNDC3B) interacts with Smad1/5/8 via its N-terminal proline-rich motif and down-regulates Smad1/5/8 phosphorylation, acting as a negative regulator of BMP/Smad signaling in calvarial cells. fad104 disruption causes craniosynostosis-like premature calvarial ossification.","method":"Co-immunoprecipitation, mutagenesis (N-terminal deletion mutants), in vitro phosphorylation assays, calvarial cell differentiation assays, knockout mouse phenotyping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein interaction (Co-IP) with domain mutagenesis and functional rescue, in vivo knockout phenotype","pmids":["24052261"],"is_preprint":false},{"year":2015,"finding":"Fad104 (FNDC3B) suppresses invasion and metastasis of melanoma cells by interacting with STAT3 and downregulating STAT3 phosphorylation. Reduction of fad104 enhanced migration/invasion; overexpression inhibited lung colonization.","method":"Co-immunoprecipitation, overexpression/knockdown, transwell invasion assays, in vivo lung colonization assay, phosphorylation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction and phosphorylation evidence with in vivo metastasis data, single lab","pmids":["25671570"],"is_preprint":false},{"year":2016,"finding":"FAD104 (FNDC3B) N-terminal region (containing proline-rich motif and transmembrane domain) is required for interaction with the C-terminal region of STAT3 and suppression of STAT3 activity and anchorage-independent growth in melanoma cells.","method":"Deletion mutant analysis, co-immunoprecipitation, colony formation assays","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with Co-IP in single lab, mechanistic follow-up of prior STAT3 interaction study","pmids":["26948083"],"is_preprint":false},{"year":2016,"finding":"FNDC3B promotes cell migration in hepatocellular carcinoma by cooperating with annexin A2 (ANXA2); mutagenesis and LC-MS/MS analyses identified this interaction, and overexpression enhanced migration/invasion while shRNA knockdown reduced metastatic nodule formation.","method":"LC-MS/MS, mutagenesis, shRNA knockdown, cell migration/invasion assays, in vivo metastasis models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LC-MS/MS interaction identification with mutagenesis and functional in vivo validation, single lab","pmids":["27385217"],"is_preprint":false},{"year":2017,"finding":"FAD104 (FNDC3B) functions as a suppressor of TGF-β-mediated EMT in cervical cancer cells: FAD104 overexpression suppresses TGF-β-induced EMT, negatively regulates phosphorylation of Smad2 and Smad3, and positively regulates phosphorylation of Smad1/5/8.","method":"Overexpression and knockdown in HeLa cells, TGF-β treatment, phosphorylation assays (western blot), EMT marker analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with specific phosphorylation readouts, single lab","pmids":["29180690"],"is_preprint":false},{"year":2013,"finding":"FNDC3B protein (not mRNA) is repressed by miR-143 in prostate cancer cells; luciferase reporter assays confirmed FNDC3B as a direct miR-143 target that regulates cell motility.","method":"Luciferase reporter assay, western blot, transwell/wound healing assays, in vivo bioluminescence imaging","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation with functional migration assays and in vivo data, single lab","pmids":["23383988"],"is_preprint":false},{"year":2016,"finding":"miR-215-5p directly targets FNDC3B (and CTNNBIP1) to impair adipocyte differentiation in 3T3-L1 cells, placing FNDC3B downstream of miR-215-5p in the regulation of early adipogenesis.","method":"Luciferase reporter assay, overexpression/knockdown, adipogenesis assays in 3T3-L1 cells","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter with functional differentiation assay, single lab, concept consistent with prior FNDC3B adipogenesis data","pmids":["27521659"],"is_preprint":false},{"year":2020,"finding":"FNDC3B binds to and stabilizes myosin heavy chain 9 (MYH9) to activate the Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma; 3'-UTR shortening via alternative polyadenylation escapes miRNA-mediated repression, causing FNDC3B overexpression.","method":"Co-immunoprecipitation, knockdown/overexpression, protein stability assays, Wnt/β-catenin reporter assays, in vitro and in vivo tumor models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional rescue and in vivo validation, single lab","pmids":["32232887"],"is_preprint":false},{"year":2022,"finding":"Hepatocyte-specific FNDC3B deletion aggravates alcohol-induced liver steatosis via AMPK inhibition. FNDC3B deletion also exacerbates ethanol-mediated lipid peroxidation and ferroptosis through AMPK inactivation, which downregulates transferrin expression and causes iron overload. FNDC3B expression is negatively regulated by miR-192-5p.","method":"Hepatocyte-specific conditional knockout mice, AMPK activity assays, RNA sequencing, ferroptosis inhibitor rescue (ferrostatin-1), primary hepatocyte studies","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout with mechanistic pathway (AMPK-transferrin-iron) validated by pharmacological rescue and RNA-seq, multiple orthogonal methods","pmids":["36336231"],"is_preprint":false},{"year":2020,"finding":"FNDC3B promotes proliferation and invasion of colorectal cancer cells via PI3K/mTOR signaling; miR-125a-5p and miR-217 directly bind FNDC3B 3'-UTR (binding motifs CUCAGGG and AUGCAGU respectively) and suppress its expression.","method":"Luciferase reporter assay, CCK-8/MTT proliferation assays, transwell invasion, western blot for PI3K/mTOR pathway components","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — luciferase reporter with functional assays and pathway validation, single lab","pmids":["32431508"],"is_preprint":false},{"year":2024,"finding":"E2F1 transcription factor directly activates FNDC3B transcription in hepatocellular carcinoma, identified via TF knockdown screening and ChIP coupled with Droplet Digital PCR; E2F1 overexpression or knockdown significantly impacts FNDC3B expression and downstream cell migration.","method":"ChIP-seq database analysis, TF knockdown screening, ChIP-ddPCR, overexpression/knockdown assays","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with ddPCR and functional knockdown validation, single lab","pmids":["38403291"],"is_preprint":false},{"year":2025,"finding":"FNDC3B interacts with FAM83H via its proline-rich N-terminus and transmembrane domain, preventing FAM83H ubiquitin-proteasomal degradation, thereby promoting gastric cancer metastasis through the FNDC3B/FAM83H/Snail/EMT axis.","method":"LC-MS/MS, co-immunoprecipitation, truncated domain mutants, immunofluorescence, ubiquitin-proteasome degradation assays, rescue experiments, in vivo xenograft models","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LC-MS/MS + Co-IP with domain mutagenesis and degradation assay, single lab","pmids":["40450207"],"is_preprint":false},{"year":2017,"finding":"miR-34a suppresses ESCC cell migration and invasion by directly targeting FNDC3B (via its 3'-UTR) as well as MMP-2 and MMP-9; luciferase reporter assays and western blot confirmed FNDC3B as a direct miR-34a target.","method":"Luciferase reporter assay, western blot, wound healing and transwell assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter with functional assays, single lab, consistent with other miRNA-targeting FNDC3B studies","pmids":["28534990"],"is_preprint":false},{"year":2015,"finding":"FNDC3B promotes EMT in tongue squamous cell carcinoma under hypoxic conditions: CoCl2 (hypoxia mimetic) upregulates FNDC3B mRNA and protein via HIF-1α, and FNDC3B knockdown suppresses migratory and invasive abilities.","method":"HIF-1α regulation study, shRNA knockdown, transwell migration/invasion assays, western blot","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional knockdown with upstream regulatory mechanism (HIF-1α), single lab, two corrigenda issued (data integrity concerns lower confidence)","pmids":["29393475"],"is_preprint":false},{"year":2026,"finding":"FNDC3B (as an ER-anchored protein expressed in Purkinje cells) facilitates climbing fiber synapse elimination in the developing mouse cerebellum from postnatal day 9–10; PC-specific conditional knockout impairs CF synapse elimination and reduces CF extension along PC dendrites at P21, with recovery by P40. Parallel fiber and inhibitory synaptic inputs are not affected.","method":"PC-specific RNAi knockdown screening, conditional knockout mice (FNDC3B-cKO), electrophysiology, morphological analysis of CF innervation","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with electrophysiology and morphology, multiple time points, specificity controls (parallel fiber inputs unaffected)","pmids":["41574767"],"is_preprint":false},{"year":2023,"finding":"RNA binding protein RBM47 binds flanking introns of FNDC3B pre-mRNA to facilitate back-splicing and generation of circFNDC3B, leading to reduction of FNDC3B mRNA levels. CircFNDC3B also inhibits FNDC3B mRNA stability by competitively binding to IGF2BP1, creating an imbalance between circFNDC3B (tumor suppressor) and FNDC3B mRNA (oncogene) in osteosarcoma.","method":"RIP assay, RNA stability analysis, RNA-FISH, immunofluorescence, qRT-PCR, functional assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP assay for RBM47-intron and IGF2BP1 interactions with RNA stability readout, single lab; note findings pertain to regulation of FNDC3B mRNA by circFNDC3B machinery","pmids":["38129874"],"is_preprint":false}],"current_model":"FNDC3B (FAD104) encodes an ER/Golgi-anchored transmembrane protein with a proline-rich N-terminus and fibronectin type III domain that acts as a positive regulator of adipogenesis, a negative regulator of osteoblast differentiation via BMP/Smad1/5/8 signaling (through direct interaction with Smad1/5/8), an essential factor for neonatal lung ATII cell maturation, and a context-dependent regulator of cell migration and EMT through interactions with ANXA2, STAT3 (suppressing its phosphorylation), MYH9 (activating Wnt/β-catenin), and FAM83H (preventing its proteasomal degradation); in the liver, FNDC3B protects against steatosis and ferroptosis via AMPK activation and transferrin regulation, and in the developing cerebellum, Purkinje cell-expressed FNDC3B facilitates climbing fiber synapse elimination during postnatal development."},"narrative":{"mechanistic_narrative":"FNDC3B (FAD104) is an ER/Golgi-anchored transmembrane protein that acts as a context-dependent regulator of cell differentiation, adhesion, and motility, with essential roles in mouse development [PMID:19138685, PMID:21704616]. It is required postnatally, as gene disruption causes rapid neonatal death from lung dysplasia, reflecting a specific requirement for FNDC3B in the maturation of alveolar type II cells and surfactant protein expression [PMID:19138685, PMID:21704616]. In mesenchymal lineage decisions FNDC3B promotes adipocyte differentiation while restraining osteoblast differentiation, the latter through its N-terminal proline-rich motif binding Smad1/5/8 and dampening their phosphorylation downstream of BMP signaling; its loss elevates Runx2 and causes craniosynostosis-like premature calvarial ossification [PMID:15527760, PMID:20493170, PMID:24052261]. FNDC3B engages multiple partners through its N-terminal region to tune migration and epithelial-mesenchymal transition: it interacts with STAT3 to suppress STAT3 phosphorylation and metastatic behavior, cooperates with annexin A2 (ANXA2) to drive carcinoma migration, stabilizes MYH9 to activate Wnt/β-catenin signaling, and binds FAM83H to block its proteasomal degradation, promoting an EMT program [PMID:24052261, PMID:25671570, PMID:26948083, PMID:27385217, PMID:32232887, PMID:40450207]. Its correct Golgi localization is required for its transforming activity, which engages PI3K/Akt and TGFβ signaling [PMID:22510613]. In the liver, hepatocyte FNDC3B protects against alcohol-induced steatosis and ferroptosis by activating AMPK and maintaining transferrin expression to prevent iron overload [PMID:36336231]. In the developing cerebellum, Purkinje-cell FNDC3B facilitates climbing fiber synapse elimination [PMID:41574767]. FNDC3B expression is tightly controlled, being activated by E2F1 and repressed by numerous microRNAs and by circFNDC3B-associated machinery [PMID:36336231, PMID:38403291, PMID:38129874].","teleology":[{"year":2004,"claim":"Established FNDC3B (FAD104) as an early, functionally required driver of adipocyte differentiation, the first assignment of a cellular role to the gene.","evidence":"RNAi knockdown and adipogenesis assays in 3T3-L1 cells","pmids":["15527760"],"confidence":"Medium","gaps":["No molecular partner or signaling mechanism identified","Restricted to a single cell-line model of adipogenesis"]},{"year":2008,"claim":"In vivo knockout revealed FNDC3B is essential for postnatal survival and showed it governs cytoskeletal organization, adhesion, spreading, migration, and proliferation in primary cells, broadening its role beyond adipogenesis.","evidence":"Gene targeting in mice, MEF adhesion/wound-healing/proliferation assays","pmids":["19138685"],"confidence":"High","gaps":["Molecular cause of neonatal lethality not yet defined","No mechanistic link between FNDC3B and stress fiber formation"]},{"year":2010,"claim":"Defined FNDC3B as a negative regulator of osteoblast differentiation, positioning it as a switch in the adipocyte-versus-osteoblast mesenchymal fate decision.","evidence":"Osteoblast differentiation assays and Runx2 western blot in knockout MEFs","pmids":["20493170"],"confidence":"Medium","gaps":["Mechanism by which FNDC3B suppresses osteogenesis not yet identified","Relationship to BMP-2 signaling not resolved at this stage"]},{"year":2011,"claim":"Pinpointed the cause of neonatal lethality to lung dysplasia, identifying FNDC3B as essential for alveolar type II cell maturation and surfactant production.","evidence":"Knockout mouse phenotyping, immunohistochemistry, surfactant protein assays","pmids":["21704616"],"confidence":"High","gaps":["Molecular pathway linking FNDC3B to ATII maturation not defined","No partner protein identified in lung context"]},{"year":2013,"claim":"Provided the first direct molecular mechanism, showing FNDC3B binds Smad1/5/8 via its N-terminal proline-rich motif to suppress BMP/Smad signaling, explaining the osteogenesis phenotype and a craniosynostosis-like skeletal defect.","evidence":"Co-IP, N-terminal deletion mutagenesis, in vitro phosphorylation, calvarial differentiation and knockout phenotyping","pmids":["24052261"],"confidence":"High","gaps":["Structural basis of the Smad interaction not determined","How an ER/Golgi-anchored protein contacts cytoplasmic Smads not resolved"]},{"year":2015,"claim":"Extended FNDC3B's interaction repertoire to STAT3, demonstrating it suppresses STAT3 phosphorylation and melanoma invasion/metastasis, establishing a tumor-suppressive context.","evidence":"Co-IP, knockdown/overexpression, transwell invasion, in vivo lung colonization","pmids":["25671570"],"confidence":"Medium","gaps":["Direct versus indirect nature of STAT3 dephosphorylation unclear","No reciprocal validation of the interaction"]},{"year":2016,"claim":"Mapped the STAT3 interaction to the FNDC3B N-terminal region (proline-rich plus transmembrane domain) and the STAT3 C-terminus, defining the structural determinants of suppression.","evidence":"Deletion mutant Co-IP and colony formation assays","pmids":["26948083"],"confidence":"Medium","gaps":["No high-resolution interface defined","Generality of the N-terminal interaction module across partners not tested"]},{"year":2016,"claim":"Revealed a pro-migratory, oncogenic role in hepatocellular carcinoma through cooperation with ANXA2, contrasting with the STAT3-suppressive context and establishing FNDC3B as context-dependent.","evidence":"LC-MS/MS, mutagenesis, shRNA knockdown, migration/invasion and in vivo metastasis assays","pmids":["27385217"],"confidence":"Medium","gaps":["Mechanism by which ANXA2 cooperation drives migration not detailed","Single-lab interaction without independent confirmation"]},{"year":2017,"claim":"Reconciled the dual role in EMT by showing FNDC3B differentially modulates TGFβ/Smad arms—suppressing Smad2/3 and promoting Smad1/5/8 phosphorylation—to inhibit TGFβ-induced EMT in cervical cancer.","evidence":"Overexpression/knockdown in HeLa cells with phospho-Smad and EMT marker readouts","pmids":["29180690"],"confidence":"Medium","gaps":["Direct substrate-level mechanism for opposing Smad regulation unknown","Reconciliation with oncogenic contexts not addressed"]},{"year":2020,"claim":"Identified two additional oncogenic effector axes: MYH9 stabilization driving Wnt/β-catenin activation in nasopharyngeal carcinoma and PI3K/mTOR-driven proliferation in colorectal cancer.","evidence":"Co-IP, protein stability and Wnt reporter assays; proliferation/invasion assays with PI3K/mTOR western blots; in vivo tumor models","pmids":["32232887","32431508"],"confidence":"Medium","gaps":["Whether MYH9 and ANXA2 use the same FNDC3B interface unknown","Single-lab findings per cancer type"]},{"year":2022,"claim":"Defined a protective metabolic function in the liver, with hepatocyte FNDC3B activating AMPK to limit steatosis and to maintain transferrin expression, thereby preventing ethanol-induced lipid peroxidation, iron overload, and ferroptosis.","evidence":"Hepatocyte-specific conditional knockout, AMPK activity assays, RNA-seq, ferrostatin-1 rescue","pmids":["36336231"],"confidence":"High","gaps":["How FNDC3B activates AMPK mechanistically unknown","Direct molecular partners in the liver not identified"]},{"year":2024,"claim":"Added a transcriptional input by showing E2F1 directly activates FNDC3B in hepatocellular carcinoma to promote migration, complementing the extensive microRNA control of the gene.","evidence":"TF knockdown screening, ChIP-ddPCR, migration assays","pmids":["38403291"],"confidence":"Medium","gaps":["Other transcriptional regulators not surveyed","Context-specificity of E2F1 control across tissues untested"]},{"year":2025,"claim":"Identified FAM83H as a partner stabilized by FNDC3B via the N-terminal proline-rich/transmembrane region, defining a FNDC3B/FAM83H/Snail/EMT axis driving gastric cancer metastasis.","evidence":"LC-MS/MS, Co-IP, domain mutants, ubiquitin-proteasome degradation assays, rescue, xenografts","pmids":["40450207"],"confidence":"Medium","gaps":["Mechanism by which FNDC3B blocks FAM83H ubiquitination unknown","Single-lab interaction"]},{"year":2026,"claim":"Uncovered a neuronal role, with Purkinje-cell FNDC3B facilitating climbing fiber synapse elimination during cerebellar development, broadening its function into the nervous system.","evidence":"PC-specific conditional knockout, electrophysiology, CF morphology across postnatal timepoints with synaptic-input specificity controls","pmids":["41574767"],"confidence":"High","gaps":["Molecular effectors mediating synapse elimination not identified","Whether known FNDC3B partners operate in neurons unknown"]},{"year":null,"claim":"It remains unresolved how a single ER/Golgi-anchored transmembrane protein mechanistically switches between tumor-suppressive (STAT3, BMP/Smad) and oncogenic (ANXA2, MYH9, FAM83H, PI3K/mTOR) outputs, and what unifies its developmental, metabolic, and neuronal roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the N-terminal interaction module","No unified explanation for context-dependent partner selection","Topology question of how a membrane-anchored protein engages diverse cytoplasmic partners"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,6,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[12,16]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,12,16]}],"complexes":[],"partners":["SMAD1","SMAD5","STAT3","ANXA2","MYH9","FAM83H"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53EP0","full_name":"Fibronectin type III domain-containing protein 3B","aliases":["Factor for adipocyte differentiation 104","HCV NS5A-binding protein 37"],"length_aa":1204,"mass_kda":132.9,"function":"May be a positive regulator of adipogenesis","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q53EP0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FNDC3B","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FNDC3B","total_profiled":1310},"omim":[{"mim_id":"611909","title":"FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 3B; FNDC3B","url":"https://www.omim.org/entry/611909"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FNDC3B"},"hgnc":{"alias_symbol":["FAD104","DKFZp762K137","FLJ23399","PRO4979","YVTM2421"],"prev_symbol":[]},"alphafold":{"accession":"Q53EP0","domains":[{"cath_id":"-","chopping":"40-103","consensus_level":"high","plddt":65.315,"start":40,"end":103},{"cath_id":"2.60.40.10","chopping":"279-299_312-375","consensus_level":"high","plddt":90.4585,"start":279,"end":375},{"cath_id":"2.60.40.10","chopping":"387-470","consensus_level":"high","plddt":88.2239,"start":387,"end":470},{"cath_id":"2.60.40.10","chopping":"483-567","consensus_level":"high","plddt":89.044,"start":483,"end":567},{"cath_id":"2.60.40.10","chopping":"577-666","consensus_level":"high","plddt":89.9156,"start":577,"end":666},{"cath_id":"2.60.40.10","chopping":"679-762","consensus_level":"high","plddt":87.5632,"start":679,"end":762},{"cath_id":"2.60.40.10","chopping":"775-856","consensus_level":"high","plddt":88.7028,"start":775,"end":856},{"cath_id":"2.60.40.10","chopping":"869-953","consensus_level":"high","plddt":82.3096,"start":869,"end":953},{"cath_id":"2.60.40.10","chopping":"965-982_990-1050","consensus_level":"high","plddt":87.0399,"start":965,"end":1050}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EP0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EP0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EP0-F1-predicted_aligned_error_v6.png","plddt_mean":75.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FNDC3B","jax_strain_url":"https://www.jax.org/strain/search?query=FNDC3B"},"sequence":{"accession":"Q53EP0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53EP0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53EP0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EP0"}},"corpus_meta":[{"pmid":"30963578","id":"PMC_30963578","title":"FNDC3B circular RNA promotes the migration and invasion of gastric cancer cells via the regulation of E-cadherin and CD44 expression.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30963578","citation_count":100,"is_preprint":false},{"pmid":"23383988","id":"PMC_23383988","title":"Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression.","date":"2013","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23383988","citation_count":86,"is_preprint":false},{"pmid":"22510613","id":"PMC_22510613","title":"Activation of multiple cancer pathways and tumor maintenance function of the 3q amplified oncogene FNDC3B.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22510613","citation_count":69,"is_preprint":false},{"pmid":"15527760","id":"PMC_15527760","title":"The novel gene fad104, containing a fibronectin type III 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Overexpression induces EMT and activates PI3K/Akt, Rb1, and TGFβ signaling pathways. For TGFβ signaling, FNDC3B induces expression of all three TGFβ ligands and promotes TGFBR1 cell-surface localization.\",\n      \"method\": \"Cellular localization assays, RNAi knockdown, overexpression in mammary/kidney epithelial cells and hepatocytes, cancer pathway activation assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, RNAi, pathway analysis) in single lab; no structural or in vitro reconstitution\",\n      \"pmids\": [\"22510613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fad104 (FNDC3B) expression is rapidly induced in early adipogenesis and functions as a positive regulator of adipocyte differentiation; knockdown by RNAi represses adipogenesis in 3T3-L1 cells.\",\n      \"method\": \"RNAi knockdown, adipogenesis assays in 3T3-L1 cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (adipogenesis), replicated concept in subsequent studies\",\n      \"pmids\": [\"15527760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Disruption of fad104 (FNDC3B) in mice causes rapid postnatal death, and fad104-deficient MEFs show reduced stress fiber formation, delayed cell adhesion, spreading, and migration, as well as inhibited adipocyte differentiation and cell proliferation.\",\n      \"method\": \"Gene targeting (knockout mice), mouse embryonic fibroblast analysis, cell adhesion assays, wound healing assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple orthogonal phenotypic readouts (proliferation, adhesion, spreading, migration) in primary cells\",\n      \"pmids\": [\"19138685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fad104 (FNDC3B) negatively regulates osteoblast differentiation: its expression decreases during osteogenesis, and fad104 deletion in MEFs facilitates osteoblast differentiation and elevates Runx2 levels. fad104 also suppresses BMP-2-mediated adipocyte differentiation.\",\n      \"method\": \"Gene knockout MEFs, osteoblast differentiation assays, western blot for Runx2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined phenotype, single lab, multiple differentiation assays\",\n      \"pmids\": [\"20493170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fad104 (FNDC3B) is essential for lung maturation: fad104-deficient mice die due to lung dysplasia (atelectasis), FAD104 is strongly expressed in ATII cells in the developing lung, and its loss impairs ATII cell maturation and surfactant-associated protein expression.\",\n      \"method\": \"Knockout mouse phenotypic analysis, immunohistochemistry, surfactant protein expression assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with specific cellular and molecular phenotype (ATII cell maturation, surfactant proteins), replicated in same knockout model\",\n      \"pmids\": [\"21704616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FAD104 (FNDC3B) interacts with Smad1/5/8 via its N-terminal proline-rich motif and down-regulates Smad1/5/8 phosphorylation, acting as a negative regulator of BMP/Smad signaling in calvarial cells. fad104 disruption causes craniosynostosis-like premature calvarial ossification.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (N-terminal deletion mutants), in vitro phosphorylation assays, calvarial cell differentiation assays, knockout mouse phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein interaction (Co-IP) with domain mutagenesis and functional rescue, in vivo knockout phenotype\",\n      \"pmids\": [\"24052261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fad104 (FNDC3B) suppresses invasion and metastasis of melanoma cells by interacting with STAT3 and downregulating STAT3 phosphorylation. Reduction of fad104 enhanced migration/invasion; overexpression inhibited lung colonization.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, transwell invasion assays, in vivo lung colonization assay, phosphorylation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction and phosphorylation evidence with in vivo metastasis data, single lab\",\n      \"pmids\": [\"25671570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAD104 (FNDC3B) N-terminal region (containing proline-rich motif and transmembrane domain) is required for interaction with the C-terminal region of STAT3 and suppression of STAT3 activity and anchorage-independent growth in melanoma cells.\",\n      \"method\": \"Deletion mutant analysis, co-immunoprecipitation, colony formation assays\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with Co-IP in single lab, mechanistic follow-up of prior STAT3 interaction study\",\n      \"pmids\": [\"26948083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FNDC3B promotes cell migration in hepatocellular carcinoma by cooperating with annexin A2 (ANXA2); mutagenesis and LC-MS/MS analyses identified this interaction, and overexpression enhanced migration/invasion while shRNA knockdown reduced metastatic nodule formation.\",\n      \"method\": \"LC-MS/MS, mutagenesis, shRNA knockdown, cell migration/invasion assays, in vivo metastasis models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS/MS interaction identification with mutagenesis and functional in vivo validation, single lab\",\n      \"pmids\": [\"27385217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAD104 (FNDC3B) functions as a suppressor of TGF-β-mediated EMT in cervical cancer cells: FAD104 overexpression suppresses TGF-β-induced EMT, negatively regulates phosphorylation of Smad2 and Smad3, and positively regulates phosphorylation of Smad1/5/8.\",\n      \"method\": \"Overexpression and knockdown in HeLa cells, TGF-β treatment, phosphorylation assays (western blot), EMT marker analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with specific phosphorylation readouts, single lab\",\n      \"pmids\": [\"29180690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FNDC3B protein (not mRNA) is repressed by miR-143 in prostate cancer cells; luciferase reporter assays confirmed FNDC3B as a direct miR-143 target that regulates cell motility.\",\n      \"method\": \"Luciferase reporter assay, western blot, transwell/wound healing assays, in vivo bioluminescence imaging\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation with functional migration assays and in vivo data, single lab\",\n      \"pmids\": [\"23383988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-215-5p directly targets FNDC3B (and CTNNBIP1) to impair adipocyte differentiation in 3T3-L1 cells, placing FNDC3B downstream of miR-215-5p in the regulation of early adipogenesis.\",\n      \"method\": \"Luciferase reporter assay, overexpression/knockdown, adipogenesis assays in 3T3-L1 cells\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter with functional differentiation assay, single lab, concept consistent with prior FNDC3B adipogenesis data\",\n      \"pmids\": [\"27521659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FNDC3B binds to and stabilizes myosin heavy chain 9 (MYH9) to activate the Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma; 3'-UTR shortening via alternative polyadenylation escapes miRNA-mediated repression, causing FNDC3B overexpression.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, protein stability assays, Wnt/β-catenin reporter assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional rescue and in vivo validation, single lab\",\n      \"pmids\": [\"32232887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatocyte-specific FNDC3B deletion aggravates alcohol-induced liver steatosis via AMPK inhibition. FNDC3B deletion also exacerbates ethanol-mediated lipid peroxidation and ferroptosis through AMPK inactivation, which downregulates transferrin expression and causes iron overload. FNDC3B expression is negatively regulated by miR-192-5p.\",\n      \"method\": \"Hepatocyte-specific conditional knockout mice, AMPK activity assays, RNA sequencing, ferroptosis inhibitor rescue (ferrostatin-1), primary hepatocyte studies\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout with mechanistic pathway (AMPK-transferrin-iron) validated by pharmacological rescue and RNA-seq, multiple orthogonal methods\",\n      \"pmids\": [\"36336231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FNDC3B promotes proliferation and invasion of colorectal cancer cells via PI3K/mTOR signaling; miR-125a-5p and miR-217 directly bind FNDC3B 3'-UTR (binding motifs CUCAGGG and AUGCAGU respectively) and suppress its expression.\",\n      \"method\": \"Luciferase reporter assay, CCK-8/MTT proliferation assays, transwell invasion, western blot for PI3K/mTOR pathway components\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — luciferase reporter with functional assays and pathway validation, single lab\",\n      \"pmids\": [\"32431508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F1 transcription factor directly activates FNDC3B transcription in hepatocellular carcinoma, identified via TF knockdown screening and ChIP coupled with Droplet Digital PCR; E2F1 overexpression or knockdown significantly impacts FNDC3B expression and downstream cell migration.\",\n      \"method\": \"ChIP-seq database analysis, TF knockdown screening, ChIP-ddPCR, overexpression/knockdown assays\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with ddPCR and functional knockdown validation, single lab\",\n      \"pmids\": [\"38403291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FNDC3B interacts with FAM83H via its proline-rich N-terminus and transmembrane domain, preventing FAM83H ubiquitin-proteasomal degradation, thereby promoting gastric cancer metastasis through the FNDC3B/FAM83H/Snail/EMT axis.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, truncated domain mutants, immunofluorescence, ubiquitin-proteasome degradation assays, rescue experiments, in vivo xenograft models\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS/MS + Co-IP with domain mutagenesis and degradation assay, single lab\",\n      \"pmids\": [\"40450207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-34a suppresses ESCC cell migration and invasion by directly targeting FNDC3B (via its 3'-UTR) as well as MMP-2 and MMP-9; luciferase reporter assays and western blot confirmed FNDC3B as a direct miR-34a target.\",\n      \"method\": \"Luciferase reporter assay, western blot, wound healing and transwell assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter with functional assays, single lab, consistent with other miRNA-targeting FNDC3B studies\",\n      \"pmids\": [\"28534990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FNDC3B promotes EMT in tongue squamous cell carcinoma under hypoxic conditions: CoCl2 (hypoxia mimetic) upregulates FNDC3B mRNA and protein via HIF-1α, and FNDC3B knockdown suppresses migratory and invasive abilities.\",\n      \"method\": \"HIF-1α regulation study, shRNA knockdown, transwell migration/invasion assays, western blot\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional knockdown with upstream regulatory mechanism (HIF-1α), single lab, two corrigenda issued (data integrity concerns lower confidence)\",\n      \"pmids\": [\"29393475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FNDC3B (as an ER-anchored protein expressed in Purkinje cells) facilitates climbing fiber synapse elimination in the developing mouse cerebellum from postnatal day 9–10; PC-specific conditional knockout impairs CF synapse elimination and reduces CF extension along PC dendrites at P21, with recovery by P40. Parallel fiber and inhibitory synaptic inputs are not affected.\",\n      \"method\": \"PC-specific RNAi knockdown screening, conditional knockout mice (FNDC3B-cKO), electrophysiology, morphological analysis of CF innervation\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with electrophysiology and morphology, multiple time points, specificity controls (parallel fiber inputs unaffected)\",\n      \"pmids\": [\"41574767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNA binding protein RBM47 binds flanking introns of FNDC3B pre-mRNA to facilitate back-splicing and generation of circFNDC3B, leading to reduction of FNDC3B mRNA levels. CircFNDC3B also inhibits FNDC3B mRNA stability by competitively binding to IGF2BP1, creating an imbalance between circFNDC3B (tumor suppressor) and FNDC3B mRNA (oncogene) in osteosarcoma.\",\n      \"method\": \"RIP assay, RNA stability analysis, RNA-FISH, immunofluorescence, qRT-PCR, functional assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP assay for RBM47-intron and IGF2BP1 interactions with RNA stability readout, single lab; note findings pertain to regulation of FNDC3B mRNA by circFNDC3B machinery\",\n      \"pmids\": [\"38129874\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FNDC3B (FAD104) encodes an ER/Golgi-anchored transmembrane protein with a proline-rich N-terminus and fibronectin type III domain that acts as a positive regulator of adipogenesis, a negative regulator of osteoblast differentiation via BMP/Smad1/5/8 signaling (through direct interaction with Smad1/5/8), an essential factor for neonatal lung ATII cell maturation, and a context-dependent regulator of cell migration and EMT through interactions with ANXA2, STAT3 (suppressing its phosphorylation), MYH9 (activating Wnt/β-catenin), and FAM83H (preventing its proteasomal degradation); in the liver, FNDC3B protects against steatosis and ferroptosis via AMPK activation and transferrin regulation, and in the developing cerebellum, Purkinje cell-expressed FNDC3B facilitates climbing fiber synapse elimination during postnatal development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FNDC3B (FAD104) is an ER/Golgi-anchored transmembrane protein that acts as a context-dependent regulator of cell differentiation, adhesion, and motility, with essential roles in mouse development [#2, #4]. It is required postnatally, as gene disruption causes rapid neonatal death from lung dysplasia, reflecting a specific requirement for FNDC3B in the maturation of alveolar type II cells and surfactant protein expression [#2, #4]. In mesenchymal lineage decisions FNDC3B promotes adipocyte differentiation while restraining osteoblast differentiation, the latter through its N-terminal proline-rich motif binding Smad1/5/8 and dampening their phosphorylation downstream of BMP signaling; its loss elevates Runx2 and causes craniosynostosis-like premature calvarial ossification [#1, #3, #5]. FNDC3B engages multiple partners through its N-terminal region to tune migration and epithelial-mesenchymal transition: it interacts with STAT3 to suppress STAT3 phosphorylation and metastatic behavior, cooperates with annexin A2 (ANXA2) to drive carcinoma migration, stabilizes MYH9 to activate Wnt/\\u03b2-catenin signaling, and binds FAM83H to block its proteasomal degradation, promoting an EMT program [#5, #6, #7, #8, #12, #16]. Its correct Golgi localization is required for its transforming activity, which engages PI3K/Akt and TGF\\u03b2 signaling [#0]. In the liver, hepatocyte FNDC3B protects against alcohol-induced steatosis and ferroptosis by activating AMPK and maintaining transferrin expression to prevent iron overload [#13]. In the developing cerebellum, Purkinje-cell FNDC3B facilitates climbing fiber synapse elimination [#19]. FNDC3B expression is tightly controlled, being activated by E2F1 and repressed by numerous microRNAs and by circFNDC3B-associated machinery [#13, #15, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established FNDC3B (FAD104) as an early, functionally required driver of adipocyte differentiation, the first assignment of a cellular role to the gene.\",\n      \"evidence\": \"RNAi knockdown and adipogenesis assays in 3T3-L1 cells\",\n      \"pmids\": [\"15527760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or signaling mechanism identified\", \"Restricted to a single cell-line model of adipogenesis\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"In vivo knockout revealed FNDC3B is essential for postnatal survival and showed it governs cytoskeletal organization, adhesion, spreading, migration, and proliferation in primary cells, broadening its role beyond adipogenesis.\",\n      \"evidence\": \"Gene targeting in mice, MEF adhesion/wound-healing/proliferation assays\",\n      \"pmids\": [\"19138685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cause of neonatal lethality not yet defined\", \"No mechanistic link between FNDC3B and stress fiber formation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined FNDC3B as a negative regulator of osteoblast differentiation, positioning it as a switch in the adipocyte-versus-osteoblast mesenchymal fate decision.\",\n      \"evidence\": \"Osteoblast differentiation assays and Runx2 western blot in knockout MEFs\",\n      \"pmids\": [\"20493170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FNDC3B suppresses osteogenesis not yet identified\", \"Relationship to BMP-2 signaling not resolved at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pinpointed the cause of neonatal lethality to lung dysplasia, identifying FNDC3B as essential for alveolar type II cell maturation and surfactant production.\",\n      \"evidence\": \"Knockout mouse phenotyping, immunohistochemistry, surfactant protein assays\",\n      \"pmids\": [\"21704616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking FNDC3B to ATII maturation not defined\", \"No partner protein identified in lung context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the first direct molecular mechanism, showing FNDC3B binds Smad1/5/8 via its N-terminal proline-rich motif to suppress BMP/Smad signaling, explaining the osteogenesis phenotype and a craniosynostosis-like skeletal defect.\",\n      \"evidence\": \"Co-IP, N-terminal deletion mutagenesis, in vitro phosphorylation, calvarial differentiation and knockout phenotyping\",\n      \"pmids\": [\"24052261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Smad interaction not determined\", \"How an ER/Golgi-anchored protein contacts cytoplasmic Smads not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended FNDC3B's interaction repertoire to STAT3, demonstrating it suppresses STAT3 phosphorylation and melanoma invasion/metastasis, establishing a tumor-suppressive context.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, transwell invasion, in vivo lung colonization\",\n      \"pmids\": [\"25671570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of STAT3 dephosphorylation unclear\", \"No reciprocal validation of the interaction\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the STAT3 interaction to the FNDC3B N-terminal region (proline-rich plus transmembrane domain) and the STAT3 C-terminus, defining the structural determinants of suppression.\",\n      \"evidence\": \"Deletion mutant Co-IP and colony formation assays\",\n      \"pmids\": [\"26948083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution interface defined\", \"Generality of the N-terminal interaction module across partners not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a pro-migratory, oncogenic role in hepatocellular carcinoma through cooperation with ANXA2, contrasting with the STAT3-suppressive context and establishing FNDC3B as context-dependent.\",\n      \"evidence\": \"LC-MS/MS, mutagenesis, shRNA knockdown, migration/invasion and in vivo metastasis assays\",\n      \"pmids\": [\"27385217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ANXA2 cooperation drives migration not detailed\", \"Single-lab interaction without independent confirmation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reconciled the dual role in EMT by showing FNDC3B differentially modulates TGF\\u03b2/Smad arms—suppressing Smad2/3 and promoting Smad1/5/8 phosphorylation—to inhibit TGF\\u03b2-induced EMT in cervical cancer.\",\n      \"evidence\": \"Overexpression/knockdown in HeLa cells with phospho-Smad and EMT marker readouts\",\n      \"pmids\": [\"29180690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate-level mechanism for opposing Smad regulation unknown\", \"Reconciliation with oncogenic contexts not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified two additional oncogenic effector axes: MYH9 stabilization driving Wnt/\\u03b2-catenin activation in nasopharyngeal carcinoma and PI3K/mTOR-driven proliferation in colorectal cancer.\",\n      \"evidence\": \"Co-IP, protein stability and Wnt reporter assays; proliferation/invasion assays with PI3K/mTOR western blots; in vivo tumor models\",\n      \"pmids\": [\"32232887\", \"32431508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MYH9 and ANXA2 use the same FNDC3B interface unknown\", \"Single-lab findings per cancer type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a protective metabolic function in the liver, with hepatocyte FNDC3B activating AMPK to limit steatosis and to maintain transferrin expression, thereby preventing ethanol-induced lipid peroxidation, iron overload, and ferroptosis.\",\n      \"evidence\": \"Hepatocyte-specific conditional knockout, AMPK activity assays, RNA-seq, ferrostatin-1 rescue\",\n      \"pmids\": [\"36336231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FNDC3B activates AMPK mechanistically unknown\", \"Direct molecular partners in the liver not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added a transcriptional input by showing E2F1 directly activates FNDC3B in hepatocellular carcinoma to promote migration, complementing the extensive microRNA control of the gene.\",\n      \"evidence\": \"TF knockdown screening, ChIP-ddPCR, migration assays\",\n      \"pmids\": [\"38403291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other transcriptional regulators not surveyed\", \"Context-specificity of E2F1 control across tissues untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FAM83H as a partner stabilized by FNDC3B via the N-terminal proline-rich/transmembrane region, defining a FNDC3B/FAM83H/Snail/EMT axis driving gastric cancer metastasis.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, domain mutants, ubiquitin-proteasome degradation assays, rescue, xenografts\",\n      \"pmids\": [\"40450207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FNDC3B blocks FAM83H ubiquitination unknown\", \"Single-lab interaction\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Uncovered a neuronal role, with Purkinje-cell FNDC3B facilitating climbing fiber synapse elimination during cerebellar development, broadening its function into the nervous system.\",\n      \"evidence\": \"PC-specific conditional knockout, electrophysiology, CF morphology across postnatal timepoints with synaptic-input specificity controls\",\n      \"pmids\": [\"41574767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effectors mediating synapse elimination not identified\", \"Whether known FNDC3B partners operate in neurons unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single ER/Golgi-anchored transmembrane protein mechanistically switches between tumor-suppressive (STAT3, BMP/Smad) and oncogenic (ANXA2, MYH9, FAM83H, PI3K/mTOR) outputs, and what unifies its developmental, metabolic, and neuronal roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the N-terminal interaction module\", \"No unified explanation for context-dependent partner selection\", \"Topology question of how a membrane-anchored protein engages diverse cytoplasmic partners\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 6, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [12, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 12, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SMAD1\", \"SMAD5\", \"STAT3\", \"ANXA2\", \"MYH9\", \"FAM83H\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}