{"gene":"FAT1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2004,"finding":"FAT1 directly interacts with Ena/VASP proteins at the leading edge of lamellipodia, filopodia, and microspike tips; when the FAT1 cytoplasmic domain is targeted to mitochondrial outer leaflets it recruits actin polymerization machinery and induces ectopic actin polymerization; FAT1 knockdown decreases VASP recruitment to the leading edge, impairs lamellipodial dynamics, and attenuates cell migration, establishing FAT1 as a proximal regulator of Ena/VASP-dependent cytoskeletal dynamics.","method":"Co-immunoprecipitation, ectopic targeting/recruitment assay, siRNA knockdown, wound-healing migration assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding shown, ectopic domain recruitment reconstituted, knockdown phenotype with specific molecular readout; replicated conceptually in a companion paper (PMID:15148305)","pmids":["15343270"],"is_preprint":false},{"year":2004,"finding":"Mammalian Fat1 localizes to filopodial tips, lamellipodial edges, and cell-cell boundaries overlapping with dynamic actin structures; RNAi-mediated knockdown disorganizes junction-associated F-actin and actin cables, disturbs cell-cell contacts, and inhibits cell polarity at wound margins; Ena/VASP proteins were identified as downstream effectors.","method":"RNAi knockdown, immunofluorescence localization, actin cytoskeleton imaging, wound-healing assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined cellular phenotype, direct localization, Ena/VASP identified as effector; corroborated by PMID:15343270","pmids":["15148305"],"is_preprint":false},{"year":2005,"finding":"The FAT1 cytoplasmic domain contains a nuclear localization signal and undergoes proteolytic processing: first the extracellular domain is cleaved, then the resulting transmembrane fragment is released to the cytosol and translocates to the nucleus, indicating regulated intramembrane proteolysis governs FAT1 intracellular signaling.","method":"EGFP fusion constructs expressed in HEK293/HeLa cells, subcellular fractionation, deletion mutagenesis of NLS","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional domain mapping, single lab, multiple constructs","pmids":["15922730"],"is_preprint":false},{"year":2006,"finding":"The Fat1 intracellular domain interacts with β-catenin, inhibiting β-catenin nuclear localization and transcriptional activity; Fat1 itself undergoes cleavage generating intracellular fragments that localize to the nucleus; Fat1 knockdown enhances cyclin D1 expression and VSMC proliferation while reducing migration, establishing a dual anti-proliferative/pro-migratory role in vascular smooth muscle cells.","method":"Co-immunoprecipitation, β-catenin reporter assay, siRNA knockdown, cyclin D1 promoter assay, migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, reporter assay, KD phenotype with defined molecular pathway; multiple orthogonal methods in one study","pmids":["16682528"],"is_preprint":false},{"year":2007,"finding":"Three novel splice isoforms of FAT1 were identified; only wild-type FAT1 localizes to the cellular leading edge via a phosphotyrosine-binding-like (DN_XYH) motif disrupted by peptide inserts in alternative isoforms; spliced isoforms localize exclusively to intercellular junctions; overexpression of FAT1(WT) induces cellular protrusions and knockdown of spliced isoforms increases wound healing, demonstrating that differential subcellular distribution of isoforms controls migratory behavior.","method":"Isoform cloning, domain mutagenesis, subcellular immunofluorescence, overexpression, siRNA knockdown, wound-healing assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of targeting motif, isoform-specific KD/OE, multiple orthogonal localization and functional readouts in one study","pmids":["17500054"],"is_preprint":false},{"year":2009,"finding":"Fat1 physically interacts with Atrophin proteins (Atr1 and Atr2); interaction requires Fat1 amino acids 4300–4400 and an intact Atro-box in Atrophins; Fat1 and Atrs co-localize at cell-cell junctions, perinuclear area, and nucleus in VSMCs; Atr1 and Atr2L have opposing effects on VSMC directional migration, and the migration-enhancing effect of Atr2L knockdown requires Fat1 expression, placing Fat1 upstream of Atrophin-mediated polarity.","method":"Co-immunoprecipitation with domain-mapping, siRNA knockdown, immunocytochemistry, migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, epistasis via KD rescue, defined cellular phenotype","pmids":["19131340"],"is_preprint":false},{"year":2011,"finding":"Human FAT1 undergoes dual proteolytic processing: furin-dependent cleavage into a non-covalent heterodimer (required for normal cell-surface expression) and, in melanoma cells, furin-independent cleavage generating a persistent 65-kDa membrane-bound cytoplasmic fragment; the uncleaved proform is additionally expressed at the melanoma cell surface; differences in processing produce distinct subcellular distributions—cell-cell junctional in keratinocytes vs. cytosolic in melanoma.","method":"Northern blot, protein inhibitor studies (furin inhibitor), Western blot, immunofluorescence/confocal microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization of processing, inhibitor and localization data, single lab","pmids":["21680732"],"is_preprint":false},{"year":2013,"finding":"FAT1 binds β-catenin and antagonizes its nuclear localization; somatic FAT1 loss-of-function mutations in glioblastoma, colorectal, and head/neck cancers promote Wnt signaling and tumorigenesis; FAT1 suppresses cancer cell growth in vitro and in vivo, identifying it as a 4q35 tumor suppressor that controls aberrant Wnt activation.","method":"Co-immunoprecipitation, in vitro growth assay, xenograft in vivo model, somatic mutation analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating β-catenin binding, in vitro and in vivo functional loss-of-function, replicated across multiple cancer types","pmids":["23354438"],"is_preprint":false},{"year":2013,"finding":"Constitutive inactivation of Fat1 in mice uncouples individual myoblast polarity within migrating chains, altering the shape of specific shoulder and face muscles; tissue-specific ablation via Pax3-cre reproduces muscle shape defects in limb but not face muscles, demonstrating a cell-autonomous role of Fat1 in migrating muscle precursor polarity.","method":"Constitutive and conditional (Pax3-cre) knockout mouse models, histological and morphological analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic ablation, defined polarity phenotype, cell-autonomous epistasis established","pmids":["23785297"],"is_preprint":false},{"year":2013,"finding":"FAT1 knockdown in high-grade glioma cells increases expression of the tumor suppressor PDCD4, which then inhibits AP-1 transcription by blocking c-Jun phosphorylation, reducing expression of AP-1 target genes (MMP3, VEGF-C, PLAU) and pro-inflammatory regulators (COX-2, IL-1β, IL-6); simultaneous silencing of PDCD4 and FAT1 reverses these effects, establishing FAT1 as an upstream regulator of the PDCD4–AP-1 inflammatory axis.","method":"siRNA knockdown (FAT1 alone and dual FAT1/PDCD4), gene expression analysis, reporter assay, migration/invasion assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by dual KD rescue, multiple target gene readouts, single lab","pmids":["22986533"],"is_preprint":false},{"year":2014,"finding":"FAT1 interacts with caspase-8, preventing caspase-8 association with the death-inducing signaling complex (DISC); FAT1 knockdown or CRISPR/Cas9 knockout sensitizes glioblastoma cells to death receptor-mediated apoptosis by enhancing procaspase-8 recruitment to the DISC and increasing formation of caspase-8-containing secondary signaling complexes.","method":"Genome-wide siRNA synthetic lethal screen, Co-immunoprecipitation of FAT1–caspase-8 complex, CRISPR/Cas9 knockout, DISC immunoprecipitation, apoptosis assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide screen, Co-IP of specific complex, CRISPR KO validation, mechanistic DISC recruitment readout","pmids":["24442637"],"is_preprint":false},{"year":2014,"finding":"ADAM10 mediates ectodomain shedding of Fat1 from pancreatic cancer cells, releasing a soluble extracellular fragment into the secretome; chemical inhibition and siRNA knockdown of ADAM10 reduce Fat1 shedding; the shed ectodomain is detectable in serum of pancreatic cancer patients.","method":"Mass spectrometry, Western blot, ADAM10 chemical inhibitor and siRNA knockdown, ELISA","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sheddase identified by KD and inhibitor, biochemical characterization of fragments, single lab","pmids":["24625754"],"is_preprint":false},{"year":2015,"finding":"FAT1 acts upstream of the Hippo pathway to activate core Hippo kinase components and antagonize TAZ; FAT1 silencing promotes nuclear-cytoplasmic shuttling of TAZ, leading to enhanced CTGF transcription and increased nuclear Smad3; TAZ knockdown reverses the effects of FAT1 depletion, connecting FAT1 to TAZ–TGF-β signaling and placing FAT1 as an upstream Hippo regulator during neuronal differentiation.","method":"Gene silencing, Hippo kinase activity assay, subcellular fractionation, reporter assay, epistasis by double KD","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double KD, multiple pathway readouts, single lab","pmids":["26104008"],"is_preprint":false},{"year":2015,"finding":"Fat1 interacts genetically and physically with Fat4 to regulate neural tube closure, cortical precursor proliferation, and apical constriction in mouse brain; proteomic analysis shows Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins; in vitro data indicate Fat1 and Fat4 form cis-heterodimers, providing a mechanism for co-ordinating distinct downstream actin and junctional pathways.","method":"Genetic epistasis (double knockout mouse), proteomic co-precipitation, in vitro cis-heterodimer assay, in utero electroporation KD","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in double-KO mice, proteomics identifying distinct interactomes, in vitro heterodimer formation, multiple orthogonal methods","pmids":["26209645"],"is_preprint":false},{"year":2016,"finding":"Fat1 fragments accumulate in VSMC mitochondria and the Fat1 intracellular domain interacts with multiple inner mitochondrial membrane proteins; SMCs lacking Fat1 consume more oxygen for ATP production, contain more aspartate, and grow faster; a mitochondria-targeted Fat1 intracellular domain largely normalizes oxygen consumption; Fat1 deletion increases activity of respiratory complexes I and II and promotes complex-I-containing supercomplex formation; inactivation of SMC Fat1 in mice potentiates vascular injury response with increased medial hyperplasia.","method":"Mitochondrial fractionation, Co-IP with mitochondrial proteins, oxygen consumption measurement, metabolomics (aspartate), mitochondria-targeted domain rescue, respiratory complex activity assay, blue-native PAGE for supercomplexes, mouse vascular injury model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted mitochondrial interaction, domain-targeted rescue, multiple orthogonal biochemical and in vivo methods, published in Nature","pmids":["27828948"],"is_preprint":false},{"year":2016,"finding":"FAT1 loss-of-function in glioma cells reduces HIF-1α expression under hypoxia by compromising EGFR-Akt signaling and increasing VHL-dependent proteasomal degradation of HIF-1α; FAT1 knockdown also reduces downstream HIF-1α target gene expression (CA9, GLUT1, VEGFA, etc.) and decreases GBM cell invasiveness, establishing FAT1 as an upstream regulator of HIF-1α stability.","method":"siRNA knockdown, EGFR-Akt pathway analysis, proteasomal degradation assay, invasion assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism dissected via pathway inhibitors and KD, single lab","pmids":["27536856"],"is_preprint":false},{"year":2016,"finding":"FAT1 loss-of-function in podocytes leads to decreased cell adhesion and migration, partially reversed by a RAC1/CDC42 activator; podocyte-specific Fat1 deletion in mice induces abnormal glomerular filtration barrier development with foot process effacement; knockdown in renal tubular cells reduces active RAC1 and CDC42 and causes lumen formation defects; fat1 knockdown in zebrafish causes pronephric cysts rescued by RAC1/CDC42 activators, placing FAT1 upstream of RAC1/CDC42 in podocyte and tubular function.","method":"Patient mutation analysis, fibroblast/podocyte adhesion/migration assay, RAC1/CDC42 activation assay, conditional knockout mouse, zebrafish morpholino knockdown with pharmacological rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (human cells, mouse KO, zebrafish), pharmacological epistasis, defined molecular pathway","pmids":["26905694"],"is_preprint":false},{"year":2018,"finding":"FAT1 assembles a multimeric Hippo signaling complex (signalome) that enables activation of core Hippo kinases (MST/LATS) by TAOKs, resulting in YAP1 inactivation; FAT1 functional loss in HNSCC causes YAP1 activation that acts as an oncogenic driver; this establishes FAT1 as a scaffold that couples upstream TAOK kinases to the canonical Hippo kinase cascade.","method":"Pancancer genomic analysis, Co-IP/complex assembly assay, kinase activity assay, YAP1 reporter assay, FAT1 loss-of-function in HNSCC cells and mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — signalome complex biochemically assembled, kinase activation measured, multiple cancer models, published in Nature Communications","pmids":["29985391"],"is_preprint":false},{"year":2018,"finding":"FAT1 loss leads to YAP/TAZ accumulation on the CDK6 promoter, driving CDK6 upregulation via the Hippo pathway; suppression of CDK6 in FAT1-deficient ER+ breast cancer cells restores sensitivity to CDK4/6 inhibitors; genomic alterations in other Hippo components also promote CDK4/6i resistance, placing FAT1 loss upstream of the YAP/TAZ–CDK6 axis of drug resistance.","method":"Genomic analysis of patient tumors, ChIP demonstrating YAP/TAZ occupancy on CDK6 promoter, CDK6 suppression rescue experiment","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP evidence for transcription factor occupancy, rescue experiment, genomic data from patient cohort corroborating mechanism","pmids":["30537512"],"is_preprint":false},{"year":2018,"finding":"Tissue-specific Fat1 ablation in mesenchyme-derived connective tissue non-cell-autonomously controls cutaneous maximus muscle progenitor spreading, myogenic differentiation, and motor innervation; Fat1 ablation in motor neurons impairs axonal growth and motor pool specification, indirectly affecting muscle progenitor progression; these tissue-specific roles demonstrate Fat1 coordinates neuromuscular morphogenesis through complementary activities in distinct cell types.","method":"Tissue-specific conditional Cre knockout (mesenchyme-Fat1, neuron-Fat1), histological and molecular phenotyping","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic ablation with defined cell-autonomous and non-cell-autonomous phenotypic readouts","pmids":["29768404"],"is_preprint":false},{"year":2020,"finding":"FAT1 loss activates a CAMK2–CD44–SRC axis promoting YAP1 nuclear translocation and ZEB1 expression (mesenchymal state), while also inactivating EZH2 to promote SOX2 expression (epithelial state), resulting in a hybrid EMT state with increased tumor stemness and metastasis; these mechanisms were established by transcriptional/chromatin profiling and proteomic analyses combined with mechanistic studies in mouse models of skin SCC.","method":"Mouse genetic deletion models (skin SCC), transcriptional profiling, chromatin profiling, proteomics, mechanistic pathway analysis (CAMK2/CD44/SRC/YAP1/EZH2)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal omics approaches plus mechanistic validation in mouse models, published in Nature","pmids":["33328637"],"is_preprint":false},{"year":2014,"finding":"Angiotensin II increases Fat1 mRNA and protein expression and promotes Fat1 translocation to the cell membrane via AT1R–ERK1/2–Nox1-derived ROS signaling; Nox1 siRNA inhibits Ang II-induced Fat1 protein expression; Fat1 knockdown inhibits Ang II-induced VSMC migration, establishing Fat1 as a downstream mediator of Ang II/Nox1/ERK1/2 signaling in VSMC migration.","method":"siRNA knockdown (Nox1 and Fat1), AT1R antagonist, antioxidant treatment, ERK1/2 inhibitor, ROS measurement, migration assay (Boyden chamber)","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic inhibitors delineating pathway, single lab","pmids":["24445059"],"is_preprint":false},{"year":2019,"finding":"FAT1 knockdown in ESCC cells enhances cisplatin resistance and stemness via Wnt/β-catenin signaling: FAT1 loss induces nuclear translocation of β-catenin, which binds to the ABCC3 promoter (by ChIP) and drives ABCC3 expression, increasing drug efflux; β-catenin inhibition reverses FAT1-KD-mediated ABCC3 upregulation.","method":"siRNA knockdown, sphere-forming assay, drug efflux assay, ChIP (β-catenin on ABCC3 promoter), Western blot","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly linking β-catenin to ABCC3 promoter downstream of FAT1, single lab","pmids":["35606602"],"is_preprint":false},{"year":2023,"finding":"Endothelial FAT1 promotes degradation of YAP/TAZ by recruiting the E3 ubiquitin ligase Mind Bomb-2 (MIB2); FAT1 interacts with MIB2 (identified by Co-IP), and this interaction mediates FAT1-induced YAP/TAZ ubiquitination; loss of endothelial FAT1 or MIB2 increases YAP/TAZ protein levels and canonical target gene expression, leading to increased endothelial proliferation and angiogenesis in vitro and in vivo.","method":"Co-immunoprecipitation (FAT1–MIB2), ubiquitination assay, endothelial-specific KO mouse models, angiogenesis models in vitro and in vivo","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying specific E3 ligase, ubiquitination assay, in vivo KO recapitulates FAT1-depletion phenotype, multiple orthogonal methods","pmids":["37031213"],"is_preprint":false},{"year":2021,"finding":"FAT1 mutations in patient-derived urinary renal epithelial cells are associated with decreased phosphorylation of MST kinase and YAP, and transcriptional upregulation of YAP target genes, linking FAT1 loss to deregulation of Hippo signaling in renal disease.","method":"Immunoblotting of patient urinary epithelial cells (qPCR and Western blot for Hippo pathway components), genetic characterization","journal":"Kidney international reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — patient-derived primary cells, pathway readout but no reconstitution or rescue experiment; replicated across multiple patients","pmids":["34013115"],"is_preprint":false},{"year":2020,"finding":"NF-κB (RelA/p65) directly binds a motif at –90 to –80 bp of the FAT1 promoter and drives FAT1 transcription in GBM cells; this was shown by promoter deletion constructs, site-directed mutagenesis of the NF-κB motif abolishing reporter activity, and ChIP confirming endogenous NF-κB occupancy; NF-κB activators (hypoxia, TNF-α, ectopic NF-κB) increase FAT1 expression, and NF-κB siRNA decreases it.","method":"Promoter deletion/reporter assay, site-directed mutagenesis, ChIP, siRNA knockdown, NF-κB activator treatments","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis + ChIP confirming direct binding, single lab but multiple orthogonal methods","pmids":["31992226"],"is_preprint":false},{"year":2019,"finding":"E2F1 occupies the FAT1 promoter and transcriptionally activates FAT1 expression; E2F1 depletion decreases FAT1 mRNA and transcriptional activity as shown by ChIP and luciferase reporter assays in ESCC cells.","method":"ChIP, luciferase reporter assay, siRNA knockdown of E2F1","journal":"Chinese journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay, single lab","pmids":["31564804"],"is_preprint":false},{"year":2021,"finding":"GPC3 (glypican-3) interacts with FAT1 on liver cancer cell surfaces; the GPC3-binding region was mapped to FAT1 residues 4013–4181 (last four EGF-like domains) by ELISA and flow cytometry; GPC3 and FAT1 co-regulate EMT-related genes (Snail, Vimentin, E-Cadherin) and HCC cell migration.","method":"Co-immunoprecipitation/binding assay, ELISA domain mapping, flow cytometry, migration assay, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped binding interaction, functional co-regulation, single lab","pmids":["33420124"],"is_preprint":false},{"year":2022,"finding":"FAT1 is identified as the target antigen in hematopoietic stem cell transplant-associated membranous nephropathy; laser microdissection/tandem mass spectrometry detected FAT1 protein deposits in glomerular basement membranes; anti-FAT1 IgG and IgG4 antibodies were detected in serum and kidney eluates of affected patients but not in PLA2R-MN controls, establishing FAT1 as an immune target in this disease.","method":"Laser microdissection and tandem mass spectrometry (MS/MS), immunohistochemistry/immunofluorescence, Western blot with eluated antibodies from kidney biopsies","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS/MS antigen identification replicated in discovery + validation cohort, antibody binding confirmed biochemically","pmids":["35321939"],"is_preprint":false}],"current_model":"FAT1 is a giant atypical protocadherin that functions as a context-dependent tumor suppressor and signaling scaffold: at the cell periphery it directly binds Ena/VASP proteins to regulate actin polymerization and directed cell migration; its intracellular domain interacts with β-catenin to suppress Wnt/nuclear β-catenin signaling; it assembles a multimeric Hippo signalome (incorporating TAOK kinases and core MST/LATS kinases) to restrain YAP/TAZ activity, with YAP/TAZ degradation further enforced through FAT1-recruited E3 ligase MIB2-mediated ubiquitination; FAT1 fragments translocate to mitochondria where they interact with respiratory complex proteins to brake mitochondrial respiration and limit cell growth; FAT1 also interacts with Atrophin proteins to control cell polarity and with caspase-8 to prevent its recruitment to the DISC, thereby modulating extrinsic apoptosis; NF-κB and E2F1 transcriptionally activate FAT1 expression, and its ectodomain is shed by ADAM10; loss of FAT1 activates a CAMK2–CD44–SRC–YAP1 axis driving hybrid EMT and tumor stemness, while its intracellular domain can shuttle to the nucleus."},"narrative":{"mechanistic_narrative":"FAT1 is a giant atypical protocadherin that operates as a context-dependent tumor suppressor and membrane-anchored signaling scaffold, coupling cell-surface adhesion to cytoskeletal, transcriptional, and metabolic control [PMID:23354438, PMID:29985391]. At the cell periphery, FAT1 localizes to lamellipodial edges, filopodial tips, and cell-cell junctions, where it directly binds Ena/VASP proteins to drive actin polymerization, lamellipodial dynamics, and directed migration; isoform-specific use of a leading-edge targeting motif partitions FAT1 between migratory and junctional pools [PMID:15343270, PMID:15148305, PMID:17500054]. FAT1 is processed by regulated proteolysis—furin-dependent maturation into a cell-surface heterodimer and release of an intracellular fragment bearing a nuclear localization signal—and its ectodomain is shed by ADAM10 [PMID:15922730, PMID:21680732, PMID:24625754]. The released intracellular domain binds β-catenin to restrain its nuclear translocation and transcriptional output, so that FAT1 loss-of-function in glioblastoma, colorectal, head/neck, and esophageal cancers activates Wnt signaling and promotes growth, stemness, and drug efflux via a β-catenin–ABCC3 axis [PMID:16682528, PMID:23354438, PMID:35606602]. In parallel, FAT1 assembles a multimeric Hippo signalome that couples TAOK kinases to the MST/LATS cascade, holding YAP/TAZ inactive; endothelial FAT1 additionally recruits the E3 ligase MIB2 to ubiquitinate and degrade YAP/TAZ, and FAT1 loss drives YAP/TAZ-dependent CDK6 induction, angiogenesis, and a CAMK2–CD44–SRC–YAP1 hybrid-EMT/stemness program [PMID:26104008, PMID:29985391, PMID:30537512, PMID:33328637, PMID:37031213]. FAT1 intracellular fragments also localize to mitochondria, where the cytoplasmic domain binds inner-membrane respiratory proteins to limit oxygen consumption, respiratory complex activity, and cell growth [PMID:27828948]. Through GTPase regulation (RAC1/CDC42), FAT1 controls polarity and morphogenesis in podocytes, renal tubules, migrating myoblasts, and the neuromuscular system, and it interacts with Atrophin proteins and forms cis-heterodimers with Fat4 to coordinate junctional and actin-regulating pathways [PMID:19131340, PMID:23785297, PMID:26209645, PMID:26905694, PMID:29768404]. FAT1 also restrains extrinsic apoptosis by sequestering caspase-8 from the DISC, and its expression is transcriptionally driven by NF-κB and E2F1 [PMID:24442637, PMID:31992226, PMID:31564804]. FAT1 is an autoantigen in hematopoietic stem cell transplant-associated membranous nephropathy [PMID:35321939].","teleology":[{"year":2004,"claim":"Established FAT1's first molecular activity—linking a giant cadherin directly to actin dynamics by showing it binds and recruits Ena/VASP proteins at the leading edge to control migration.","evidence":"Co-IP, ectopic mitochondrial-targeting recruitment assay, siRNA knockdown and wound-healing in mammalian cells","pmids":["15343270","15148305"],"confidence":"High","gaps":["Did not define how FAT1 ligand engagement at the surface triggers Ena/VASP recruitment","No structural detail of the FAT1–Ena/VASP interface"]},{"year":2005,"claim":"Showed that FAT1 signals via regulated intramembrane proteolysis, releasing an NLS-bearing intracellular fragment to the nucleus, providing the mechanistic basis for downstream transcriptional control.","evidence":"EGFP-fusion constructs, subcellular fractionation, and NLS deletion mutagenesis in HEK293/HeLa","pmids":["15922730"],"confidence":"Medium","gaps":["Protease(s) responsible for intracellular cleavage not identified","Endogenous nuclear function of the fragment not demonstrated"]},{"year":2006,"claim":"Identified β-catenin as a FAT1 intracellular partner, defining how FAT1 antagonizes Wnt/nuclear β-catenin signaling and balances proliferation against migration.","evidence":"Reciprocal Co-IP, β-catenin and cyclin D1 reporter assays, siRNA knockdown in vascular smooth muscle cells","pmids":["16682528"],"confidence":"High","gaps":["Did not establish whether nuclear FAT1 fragment or membrane FAT1 mediates β-catenin sequestration","Generality beyond VSMCs untested at this stage"]},{"year":2007,"claim":"Explained how alternative splicing partitions FAT1 function, with a phosphotyrosine-binding-like motif directing wild-type FAT1 to the leading edge versus junctions for spliced isoforms.","evidence":"Isoform cloning, targeting-motif mutagenesis, isoform-specific knockdown/overexpression and wound-healing","pmids":["17500054"],"confidence":"High","gaps":["Tissue/context regulation of isoform choice not defined","Binding partner of the DN_XYH motif not identified"]},{"year":2009,"claim":"Placed FAT1 upstream of Atrophin-mediated polarity by mapping a direct FAT1–Atrophin interaction and showing Atrophin migration effects require FAT1.","evidence":"Domain-mapped reciprocal Co-IP, siRNA epistasis, and migration assays in VSMCs","pmids":["19131340"],"confidence":"High","gaps":["Transcriptional targets of FAT1–Atrophin complex not defined","Opposing Atr1/Atr2 effects mechanistically unresolved"]},{"year":2011,"claim":"Characterized FAT1 maturation, showing furin-dependent heterodimer formation for surface expression versus aberrant furin-independent processing in melanoma that alters subcellular distribution.","evidence":"Furin inhibitor studies, Western blot, and confocal localization in keratinocytes and melanoma cells","pmids":["21680732"],"confidence":"Medium","gaps":["Functional consequence of melanoma-specific cytoplasmic fragment not tested","Single-lab biochemical characterization"]},{"year":2013,"claim":"Defined FAT1 as a recurrently mutated 4q35 tumor suppressor that restrains Wnt/β-catenin-driven tumorigenesis across multiple cancers.","evidence":"Co-IP, in vitro growth and xenograft assays, and somatic mutation analysis in glioblastoma, colorectal, and head/neck cancers","pmids":["23354438"],"confidence":"High","gaps":["Did not yet integrate Wnt control with Hippo or other FAT1 pathways","Mechanism of mutation-driven loss of β-catenin antagonism not structurally resolved"]},{"year":2013,"claim":"Demonstrated a cell-autonomous role for Fat1 in polarity of migrating muscle precursors, extending FAT1 polarity function to developmental morphogenesis in vivo.","evidence":"Constitutive and Pax3-cre conditional knockout mice with morphological muscle analysis","pmids":["23785297"],"confidence":"High","gaps":["Molecular effector linking Fat1 to myoblast polarity in vivo not defined","Differential limb vs face dependence unexplained"]},{"year":2013,"claim":"Connected FAT1 to an inflammatory transcription axis by showing FAT1 loss derepresses PDCD4 to suppress AP-1 target and pro-inflammatory gene expression in glioma.","evidence":"Single and dual FAT1/PDCD4 siRNA knockdown, reporter and gene-expression analysis, invasion assays","pmids":["22986533"],"confidence":"Medium","gaps":["Direct link between FAT1 and PDCD4 regulation unresolved","Single lab, single tumor type"]},{"year":2014,"claim":"Revealed an apoptosis-modulating role: FAT1 sequesters caspase-8 from the DISC, so FAT1 loss sensitizes cells to death-receptor apoptosis.","evidence":"Genome-wide synthetic-lethal siRNA screen, Co-IP, CRISPR knockout, and DISC immunoprecipitation in glioblastoma","pmids":["24442637"],"confidence":"High","gaps":["Structural basis of FAT1–caspase-8 sequestration not defined","Whether membrane or fragment FAT1 mediates this is unclear"]},{"year":2014,"claim":"Identified ADAM10 as the FAT1 sheddase, defining ectodomain release as a regulated event detectable as a circulating fragment.","evidence":"Mass spectrometry of secretome, ADAM10 inhibitor and siRNA, ELISA on patient serum","pmids":["24625754"],"confidence":"Medium","gaps":["Functional role of shed ectodomain not demonstrated","Link between shedding and intracellular signaling not established"]},{"year":2014,"claim":"Placed Fat1 downstream of Ang II/Nox1/ERK signaling, showing it is both transcriptionally induced and membrane-translocated to mediate VSMC migration.","evidence":"Nox1/Fat1 siRNA, AT1R antagonist, ERK inhibitor, ROS measurement, Boyden-chamber migration","pmids":["24445059"],"confidence":"Medium","gaps":["Mechanism of signal-induced membrane translocation not defined","Single lab pharmacological dissection"]},{"year":2015,"claim":"First positioned FAT1 upstream of the Hippo pathway, activating core kinases to antagonize TAZ and its TGF-β/Smad3 crosstalk during neuronal differentiation.","evidence":"Gene silencing, Hippo kinase activity assay, fractionation, reporter assays, and double-knockdown epistasis","pmids":["26104008"],"confidence":"Medium","gaps":["Did not yet identify the scaffold mechanism coupling FAT1 to Hippo kinases","Single lab, single differentiation context"]},{"year":2015,"claim":"Showed Fat1 and Fat4 form cis-heterodimers and bind distinct actin/junctional interactomes to coordinate neural tube closure and cortical morphogenesis.","evidence":"Double-knockout mouse genetics, proteomic co-precipitation, in vitro heterodimer assay, in utero electroporation","pmids":["26209645"],"confidence":"High","gaps":["Functional contribution of each interactome to specific phenotypes not separated","Structural basis of cis-heterodimerization unresolved"]},{"year":2016,"claim":"Uncovered a metabolic function: FAT1 fragments enter mitochondria and bind respiratory proteins to brake oxidative phosphorylation and limit growth.","evidence":"Mitochondrial fractionation, Co-IP, oxygen consumption, metabolomics, mitochondria-targeted domain rescue, blue-native PAGE, and vascular injury mouse model","pmids":["27828948"],"confidence":"High","gaps":["How FAT1 fragments are routed to mitochondria not defined","Identity of the rate-limiting respiratory targets incompletely mapped"]},{"year":2016,"claim":"Connected FAT1 to hypoxic signaling, showing FAT1 sustains HIF-1α via EGFR-Akt and protects it from VHL-dependent degradation in glioma.","evidence":"siRNA knockdown, EGFR-Akt pathway and proteasomal degradation analysis, invasion assays","pmids":["27536856"],"confidence":"Medium","gaps":["Direct mechanism linking FAT1 to EGFR-Akt not defined","Single lab, single tumor type"]},{"year":2016,"claim":"Established FAT1 as an upstream RAC1/CDC42 regulator required for podocyte and tubular adhesion, migration, and lumen/barrier morphogenesis.","evidence":"Patient mutations, adhesion/migration assays, RAC1/CDC42 activation assays, conditional knockout mice, zebrafish knockdown with pharmacological rescue","pmids":["26905694"],"confidence":"High","gaps":["Direct effector linking FAT1 to RAC1/CDC42 activation not identified","Relationship to FAT1's Ena/VASP cytoskeletal arm unresolved"]},{"year":2018,"claim":"Resolved the FAT1–Hippo mechanism by showing FAT1 assembles a signalome scaffold coupling TAOK kinases to MST/LATS to inactivate YAP1, with loss acting as an oncogenic driver.","evidence":"Pan-cancer genomics, Co-IP/complex assembly, kinase and YAP1 reporter assays, FAT1 loss in HNSCC cells and mouse models","pmids":["29985391"],"confidence":"High","gaps":["Stoichiometry and structure of the signalome not defined","Trigger that nucleates assembly at the membrane unclear"]},{"year":2018,"claim":"Linked FAT1 loss to therapy resistance via the Hippo–YAP/TAZ–CDK6 axis, explaining CDK4/6 inhibitor resistance in ER+ breast cancer.","evidence":"Patient genomics, ChIP for YAP/TAZ on the CDK6 promoter, and CDK6 suppression rescue","pmids":["30537512"],"confidence":"High","gaps":["Whether FAT1 directly or indirectly sets CDK6 promoter occupancy not separated","Generalizability beyond ER+ breast cancer untested here"]},{"year":2018,"claim":"Demonstrated cell-autonomous and non-cell-autonomous Fat1 roles coordinating muscle progenitor spreading, differentiation, and motor innervation across mesenchyme and neurons.","evidence":"Tissue-specific conditional Cre knockouts with histological and molecular phenotyping","pmids":["29768404"],"confidence":"High","gaps":["Signal mediating non-cell-autonomous control of progenitors not identified","Molecular link to FAT1 polarity machinery not mapped"]},{"year":2019,"claim":"Identified E2F1 as a transcriptional activator of FAT1, adding cell-cycle-coupled control of FAT1 expression.","evidence":"ChIP, luciferase reporter, and E2F1 siRNA in ESCC cells","pmids":["31564804"],"confidence":"Medium","gaps":["Physiological conditions driving E2F1-dependent FAT1 induction not defined","Single lab"]},{"year":2020,"claim":"Integrated FAT1 loss into a hybrid-EMT/stemness program through a CAMK2–CD44–SRC–YAP1 axis and EZH2 inactivation, explaining its pro-metastatic effects on tumor plasticity.","evidence":"Skin SCC mouse genetic models with transcriptional, chromatin, and proteomic profiling and pathway validation","pmids":["33328637"],"confidence":"High","gaps":["How FAT1 normally restrains CAMK2 activation not defined","Relative contributions of the epithelial vs mesenchymal arms to metastasis unresolved"]},{"year":2020,"claim":"Identified NF-κB (RelA/p65) as a direct transcriptional activator of FAT1, linking inflammatory/hypoxic stimuli to FAT1 expression in glioblastoma.","evidence":"Promoter deletion/mutagenesis, ChIP, siRNA knockdown, and NF-κB activator treatments","pmids":["31992226"],"confidence":"High","gaps":["Functional consequence of NF-κB-driven FAT1 induction for tumor behavior not tested","Single lab"]},{"year":2021,"claim":"Confirmed in patient cells that FAT1 mutation deregulates Hippo signaling, with reduced MST/YAP phosphorylation and YAP target upregulation in renal disease.","evidence":"Immunoblotting and qPCR of patient-derived urinary renal epithelial cells","pmids":["34013115"],"confidence":"Medium","gaps":["No reconstitution or rescue to prove causality","Patient-derived correlative data only"]},{"year":2021,"claim":"Mapped a direct FAT1–GPC3 surface interaction co-regulating EMT genes and migration in liver cancer, identifying a cell-surface FAT1 ligand partner.","evidence":"Binding/Co-IP, ELISA domain mapping, flow cytometry, and migration/gene-expression assays in HCC cells","pmids":["33420124"],"confidence":"Medium","gaps":["Whether GPC3 binding alters FAT1 intracellular signaling not tested","Single lab"]},{"year":2022,"claim":"Established FAT1 as a disease autoantigen in hematopoietic stem cell transplant-associated membranous nephropathy.","evidence":"Laser microdissection MS/MS, immunostaining, and Western blot with eluted patient antibodies in discovery and validation cohorts","pmids":["35321939"],"confidence":"High","gaps":["Mechanism by which anti-FAT1 antibodies cause glomerular injury not defined","Trigger of FAT1 autoimmunity unknown"]},{"year":2022,"claim":"Defined a FAT1-loss drug-resistance mechanism in esophageal cancer via β-catenin-driven ABCC3 transcription enhancing drug efflux and stemness.","evidence":"siRNA knockdown, sphere-forming and drug-efflux assays, and ChIP for β-catenin on the ABCC3 promoter","pmids":["35606602"],"confidence":"Medium","gaps":["Direct vs indirect FAT1 control of β-catenin promoter binding not separated","Single lab"]},{"year":2023,"claim":"Identified MIB2 as a FAT1-recruited E3 ligase that ubiquitinates and degrades YAP/TAZ, adding a degradation arm to FAT1's Hippo control in endothelial cells.","evidence":"Co-IP, ubiquitination assays, and endothelial-specific knockout mice with angiogenesis models","pmids":["37031213"],"confidence":"High","gaps":["How FAT1 recruits MIB2 to YAP/TAZ structurally unresolved","Relationship to the FAT1–TAOK–MST/LATS kinase arm not integrated"]},{"year":null,"claim":"It remains unresolved how FAT1's distinct functional arms—Ena/VASP-driven actin dynamics, β-catenin/Wnt antagonism, Hippo signalome assembly with MIB2-mediated YAP/TAZ degradation, RAC1/CDC42-dependent polarity, mitochondrial respiratory braking, and caspase-8 sequestration—are coordinated by a single receptor and switched by proteolytic processing or ligand engagement.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural or stoichiometric model integrating FAT1's multiple intracellular complexes","The signal/ligand that toggles between FAT1's signaling modes is undefined","How processing-derived fragments are partitioned among nucleus, mitochondria, and membrane is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,17,27]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[17,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,3,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6,27]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,12,17,18,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,20,28]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,13,19,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14]}],"complexes":["FAT1 Hippo signalome (TAOK–MST/LATS)","death-inducing signaling complex (DISC, via caspase-8)","Fat1–Fat4 cis-heterodimer"],"partners":["CTNNB1","MIB2","CASP8","YAP1","TAZ","ATN1","FAT4","GPC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14517","full_name":"Protocadherin Fat 1","aliases":["Cadherin family member 7","Cadherin-related tumor suppressor homolog","Protein fat homolog"],"length_aa":4588,"mass_kda":506.3,"function":"Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14517/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAT1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAT1","total_profiled":1310},"omim":[{"mim_id":"618642","title":"SH3 DOMAIN-CONTAINING RING FINGER PROTEIN 1; SH3RF1","url":"https://www.omim.org/entry/618642"},{"mim_id":"612483","title":"FAT ATYPICAL CADHERIN 3; FAT3","url":"https://www.omim.org/entry/612483"},{"mim_id":"612411","title":"FAT ATYPICAL CADHERIN 4; FAT4","url":"https://www.omim.org/entry/612411"},{"mim_id":"604269","title":"FAT ATYPICAL CADHERIN 2; FAT2","url":"https://www.omim.org/entry/604269"},{"mim_id":"600976","title":"FAT ATYPICAL CADHERIN 1; FAT1","url":"https://www.omim.org/entry/600976"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":81.8}],"url":"https://www.proteinatlas.org/search/FAT1"},"hgnc":{"alias_symbol":["CDHF7","CDHR8"],"prev_symbol":["FAT"]},"alphafold":{"accession":"Q14517","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14517","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAT1","jax_strain_url":"https://www.jax.org/strain/search?query=FAT1"},"sequence":{"accession":"Q14517","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14517.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14517/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14517"}},"corpus_meta":[{"pmid":"30537512","id":"PMC_30537512","title":"Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway.","date":"2018","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/30537512","citation_count":411,"is_preprint":false},{"pmid":"33328637","id":"PMC_33328637","title":"Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33328637","citation_count":341,"is_preprint":false},{"pmid":"23354438","id":"PMC_23354438","title":"Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23354438","citation_count":294,"is_preprint":false},{"pmid":"15343270","id":"PMC_15343270","title":"Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15343270","citation_count":153,"is_preprint":false},{"pmid":"29985391","id":"PMC_29985391","title":"Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29985391","citation_count":149,"is_preprint":false},{"pmid":"15148305","id":"PMC_15148305","title":"Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15148305","citation_count":140,"is_preprint":false},{"pmid":"9660783","id":"PMC_9660783","title":"Disruption of the Saccharomyces cerevisiae FAT1 gene decreases very long-chain fatty acyl-CoA synthetase activity and elevates intracellular very long-chain fatty acid concentrations.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9660783","citation_count":131,"is_preprint":false},{"pmid":"21330635","id":"PMC_21330635","title":"High pancreatic n-3 fatty acids prevent STZ-induced diabetes in fat-1 mice: inflammatory pathway inhibition.","date":"2011","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/21330635","citation_count":122,"is_preprint":false},{"pmid":"12052836","id":"PMC_12052836","title":"Fatty acid transport in Saccharomyces cerevisiae. Directed mutagenesis of FAT1 distinguishes the biochemical activities associated with Fat1p.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12052836","citation_count":111,"is_preprint":false},{"pmid":"28366557","id":"PMC_28366557","title":"FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK/ERK signaling pathway in esophageal squamous cell cancer.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28366557","citation_count":96,"is_preprint":false},{"pmid":"26905694","id":"PMC_26905694","title":"FAT1 mutations cause a glomerulotubular nephropathy.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26905694","citation_count":94,"is_preprint":false},{"pmid":"16682528","id":"PMC_16682528","title":"The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16682528","citation_count":86,"is_preprint":false},{"pmid":"35321939","id":"PMC_35321939","title":"Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1.","date":"2022","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/35321939","citation_count":86,"is_preprint":false},{"pmid":"29099504","id":"PMC_29099504","title":"Atypical fibroxanthoma and pleomorphic dermal sarcoma harbor frequent NOTCH1/2 and FAT1 mutations and similar DNA copy number alteration profiles.","date":"2017","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/29099504","citation_count":79,"is_preprint":false},{"pmid":"9988704","id":"PMC_9988704","title":"The Saccharomyces cerevisiae FAT1 gene encodes an acyl-CoA synthetase that is required for maintenance of very long chain fatty acid levels.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9988704","citation_count":72,"is_preprint":false},{"pmid":"28994107","id":"PMC_28994107","title":"FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28994107","citation_count":71,"is_preprint":false},{"pmid":"16865240","id":"PMC_16865240","title":"Comparative integromics on FAT1, FAT2, FAT3 and FAT4.","date":"2006","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16865240","citation_count":70,"is_preprint":false},{"pmid":"23785297","id":"PMC_23785297","title":"Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23785297","citation_count":68,"is_preprint":false},{"pmid":"22986533","id":"PMC_22986533","title":"FAT1 acts as an upstream regulator of oncogenic and inflammatory pathways, via PDCD4, in glioma cells.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22986533","citation_count":63,"is_preprint":false},{"pmid":"21617878","id":"PMC_21617878","title":"Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21617878","citation_count":61,"is_preprint":false},{"pmid":"30102337","id":"PMC_30102337","title":"FAT1 somatic mutations in head and neck carcinoma are associated with tumor progression and survival.","date":"2018","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30102337","citation_count":59,"is_preprint":false},{"pmid":"22131549","id":"PMC_22131549","title":"Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in Fat-1 mice.","date":"2011","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/22131549","citation_count":58,"is_preprint":false},{"pmid":"26209645","id":"PMC_26209645","title":"Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26209645","citation_count":56,"is_preprint":false},{"pmid":"27828948","id":"PMC_27828948","title":"Control of mitochondrial function and cell growth by the atypical cadherin Fat1.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27828948","citation_count":55,"is_preprint":false},{"pmid":"20655721","id":"PMC_20655721","title":"Cox-2 expression, PGE(2) and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice.","date":"2010","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20655721","citation_count":54,"is_preprint":false},{"pmid":"24445059","id":"PMC_24445059","title":"Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation.","date":"2014","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/24445059","citation_count":53,"is_preprint":false},{"pmid":"33777221","id":"PMC_33777221","title":"Role of FAT1 in health and disease.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33777221","citation_count":51,"is_preprint":false},{"pmid":"35965328","id":"PMC_35965328","title":"The diverse functions of FAT1 in cancer progression: good, bad, or ugly?","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35965328","citation_count":51,"is_preprint":false},{"pmid":"31028364","id":"PMC_31028364","title":"Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified.","date":"2019","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/31028364","citation_count":47,"is_preprint":false},{"pmid":"19136374","id":"PMC_19136374","title":"Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids.","date":"2009","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19136374","citation_count":46,"is_preprint":false},{"pmid":"21680732","id":"PMC_21680732","title":"Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21680732","citation_count":45,"is_preprint":false},{"pmid":"24442637","id":"PMC_24442637","title":"A synthetic lethal screen identifies FAT1 as an antagonist of caspase-8 in extrinsic apoptosis.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/24442637","citation_count":43,"is_preprint":false},{"pmid":"26104008","id":"PMC_26104008","title":"FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/26104008","citation_count":43,"is_preprint":false},{"pmid":"24590895","id":"PMC_24590895","title":"Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma.","date":"2014","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24590895","citation_count":42,"is_preprint":false},{"pmid":"27693639","id":"PMC_27693639","title":"Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27693639","citation_count":40,"is_preprint":false},{"pmid":"18852124","id":"PMC_18852124","title":"Expression of the fat-1 gene diminishes prostate cancer growth in vivo through enhancing apoptosis and inhibiting GSK-3 beta phosphorylation.","date":"2008","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18852124","citation_count":40,"is_preprint":false},{"pmid":"27536856","id":"PMC_27536856","title":"FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27536856","citation_count":38,"is_preprint":false},{"pmid":"19131340","id":"PMC_19131340","title":"Atrophin proteins interact with the Fat1 cadherin and regulate migration and orientation in vascular smooth muscle cells.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19131340","citation_count":37,"is_preprint":false},{"pmid":"26018399","id":"PMC_26018399","title":"Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy.","date":"2015","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26018399","citation_count":36,"is_preprint":false},{"pmid":"15922730","id":"PMC_15922730","title":"Processing of the human protocadherin Fat1 and translocation of its cytoplasmic domain to the nucleus.","date":"2005","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15922730","citation_count":36,"is_preprint":false},{"pmid":"37031213","id":"PMC_37031213","title":"Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37031213","citation_count":35,"is_preprint":false},{"pmid":"31783581","id":"PMC_31783581","title":"Targeting FAT1 Inhibits Carcinogenesis, Induces Oxidative Stress and Enhances Cisplatin Sensitivity through Deregulation of LRP5/WNT2/GSS Signaling Axis in Oral Squamous Cell Carcinoma.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31783581","citation_count":35,"is_preprint":false},{"pmid":"32011035","id":"PMC_32011035","title":"Novel ASAP1-USP6, FAT1-USP6, SAR1A-USP6, and TNC-USP6 fusions in primary aneurysmal bone cyst.","date":"2020","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32011035","citation_count":34,"is_preprint":false},{"pmid":"25615407","id":"PMC_25615407","title":"Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype.","date":"2015","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/25615407","citation_count":34,"is_preprint":false},{"pmid":"24211484","id":"PMC_24211484","title":"Elevated tissue omega-3 fatty acid status prevents age-related glucose intolerance in fat-1 transgenic mice.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24211484","citation_count":34,"is_preprint":false},{"pmid":"33420124","id":"PMC_33420124","title":"Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33420124","citation_count":33,"is_preprint":false},{"pmid":"31123786","id":"PMC_31123786","title":"Radiogenomics in head and neck cancer: correlation of radiomic heterogeneity and somatic mutations in TP53, FAT1 and KMT2D.","date":"2019","source":"Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]","url":"https://pubmed.ncbi.nlm.nih.gov/31123786","citation_count":32,"is_preprint":false},{"pmid":"24052576","id":"PMC_24052576","title":"Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice.","date":"2013","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24052576","citation_count":32,"is_preprint":false},{"pmid":"27328312","id":"PMC_27328312","title":"FAT1: a potential target for monoclonal antibody therapy in colon cancer.","date":"2016","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27328312","citation_count":31,"is_preprint":false},{"pmid":"30862798","id":"PMC_30862798","title":"Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30862798","citation_count":31,"is_preprint":false},{"pmid":"17121606","id":"PMC_17121606","title":"Characterization of the porcine FABP5 gene and its association with the FAT1 QTL in an Iberian by Landrace cross.","date":"2006","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17121606","citation_count":30,"is_preprint":false},{"pmid":"29228735","id":"PMC_29228735","title":"Verteporfin inhibits gastric cancer cell growth by suppressing adhesion molecule FAT1.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29228735","citation_count":30,"is_preprint":false},{"pmid":"30589501","id":"PMC_30589501","title":"Modulation of apoptosis-related microRNAs following myocardial infarction in fat-1 transgenic mice vs wild-type mice.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30589501","citation_count":30,"is_preprint":false},{"pmid":"16581652","id":"PMC_16581652","title":"Immunohistological localisation of human FAT1 (hFAT) protein in 326 breast cancers. Does this adhesion molecule have a role in pathogenesis?","date":"2006","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16581652","citation_count":30,"is_preprint":false},{"pmid":"16014031","id":"PMC_16014031","title":"Role of Fat1 in cell-cell contact formation of podocytes in puromycin aminonucleoside nephrosis and neonatal kidney.","date":"2005","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/16014031","citation_count":29,"is_preprint":false},{"pmid":"35739249","id":"PMC_35739249","title":"Favorable immune checkpoint inhibitor outcome of patients with melanoma and NSCLC harboring FAT1 mutations.","date":"2022","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35739249","citation_count":29,"is_preprint":false},{"pmid":"30416985","id":"PMC_30416985","title":"Vaccination With a FAT1-Derived B Cell Epitope Combined With Tumor-Specific B and T Cell Epitopes Elicits Additive Protection in Cancer Mouse Models.","date":"2018","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30416985","citation_count":29,"is_preprint":false},{"pmid":"28861323","id":"PMC_28861323","title":"POU2F1 promotes growth and metastasis of hepatocellular carcinoma through the FAT1 signaling pathway.","date":"2017","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28861323","citation_count":28,"is_preprint":false},{"pmid":"24625754","id":"PMC_24625754","title":"A soluble form of the giant cadherin Fat1 is released from pancreatic cancer cells by ADAM10 mediated ectodomain shedding.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24625754","citation_count":28,"is_preprint":false},{"pmid":"29563188","id":"PMC_29563188","title":"Site-Specific Fat-1 Knock-In Enables Significant Decrease of n-6PUFAs/n-3PUFAs Ratio in Pigs.","date":"2018","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29563188","citation_count":27,"is_preprint":false},{"pmid":"24832481","id":"PMC_24832481","title":"Double transgenesis of humanized fat1 and fat2 genes promotes omega-3 polyunsaturated fatty acids synthesis in a zebrafish model.","date":"2014","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24832481","citation_count":26,"is_preprint":false},{"pmid":"29802684","id":"PMC_29802684","title":"CRISPR/Cas9-mediated specific integration of fat-1 at the goat MSTN locus.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/29802684","citation_count":25,"is_preprint":false},{"pmid":"17500054","id":"PMC_17500054","title":"Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17500054","citation_count":25,"is_preprint":false},{"pmid":"34167951","id":"PMC_34167951","title":"The Proteomic Landscape of Growth Factor Signaling Networks Associated with FAT1 Mutations in Head and Neck Cancers.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34167951","citation_count":25,"is_preprint":false},{"pmid":"35003269","id":"PMC_35003269","title":"CircRNA FAT1 Regulates Osteoblastic Differentiation of Periodontal Ligament Stem Cells via miR-4781-3p/SMAD5 Pathway.","date":"2021","source":"Stem cells international","url":"https://pubmed.ncbi.nlm.nih.gov/35003269","citation_count":25,"is_preprint":false},{"pmid":"26503303","id":"PMC_26503303","title":"High ω3-polyunsaturated fatty acids in fat-1 mice prevent streptozotocin-induced Purkinje cell degeneration through BDNF-mediated autophagy.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26503303","citation_count":24,"is_preprint":false},{"pmid":"31564804","id":"PMC_31564804","title":"FAT1, a direct transcriptional target of E2F1, suppresses cell proliferation, migration and invasion in esophageal squamous cell carcinoma.","date":"2019","source":"Chinese journal of cancer research = Chung-kuo yen cheng yen chiu","url":"https://pubmed.ncbi.nlm.nih.gov/31564804","citation_count":23,"is_preprint":false},{"pmid":"35720420","id":"PMC_35720420","title":"Upregulation of Atypical Cadherin FAT1 Promotes an Immunosuppressive Tumor Microenvironment via TGF-β.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35720420","citation_count":22,"is_preprint":false},{"pmid":"31933769","id":"PMC_31933769","title":"FAT1 inhibits the proliferation and metastasis of cervical cancer cells by binding β-catenin.","date":"2019","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31933769","citation_count":22,"is_preprint":false},{"pmid":"24019303","id":"PMC_24019303","title":"Effects of n-3 PUFA on the CD4⁺ type 2 helper T-cell-mediated immune responses in Fat-1 mice.","date":"2013","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/24019303","citation_count":22,"is_preprint":false},{"pmid":"39401356","id":"PMC_39401356","title":"Gene therapy for fat-1 prevents obesity-induced metabolic dysfunction, cellular senescence, and osteoarthritis.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39401356","citation_count":21,"is_preprint":false},{"pmid":"29565465","id":"PMC_29565465","title":"FAT1 inhibits cell migration and invasion by affecting cellular mechanical properties in esophageal squamous cell carcinoma.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29565465","citation_count":21,"is_preprint":false},{"pmid":"30624777","id":"PMC_30624777","title":"Arecoline N-oxide regulates oral squamous cell carcinoma development through NOTCH1 and FAT1 expressions.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30624777","citation_count":21,"is_preprint":false},{"pmid":"35606602","id":"PMC_35606602","title":"FAT1 downregulation enhances stemness and cisplatin resistance in esophageal squamous cell carcinoma.","date":"2022","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35606602","citation_count":20,"is_preprint":false},{"pmid":"35646625","id":"PMC_35646625","title":"FAT1 Upregulates in Oral Squamous Cell Carcinoma and Promotes Cell Proliferation via Cell Cycle and DNA Repair.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35646625","citation_count":20,"is_preprint":false},{"pmid":"29768404","id":"PMC_29768404","title":"Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/29768404","citation_count":20,"is_preprint":false},{"pmid":"33890248","id":"PMC_33890248","title":"S100A14 inhibits cell growth and epithelial-mesenchymal transition (EMT) in prostate cancer through FAT1-mediated Hippo signaling pathway.","date":"2021","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/33890248","citation_count":20,"is_preprint":false},{"pmid":"29679557","id":"PMC_29679557","title":"Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice endogenously synthesizing long-chain n-3 fatty acids.","date":"2018","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29679557","citation_count":20,"is_preprint":false},{"pmid":"34939311","id":"PMC_34939311","title":"Clinical significance of FAT1 gene mutation and mRNA expression in patients with head and neck squamous cell carcinoma.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34939311","citation_count":18,"is_preprint":false},{"pmid":"26373379","id":"PMC_26373379","title":"Negatively charged AuNP modified with monoclonal antibody against novel tumor antigen FAT1 for tumor targeting.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/26373379","citation_count":18,"is_preprint":false},{"pmid":"17032783","id":"PMC_17032783","title":"Adipocyte fatty-acid binding protein is closely associated to the porcine FAT1 locus on chromosome 4.","date":"2006","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/17032783","citation_count":18,"is_preprint":false},{"pmid":"31992226","id":"PMC_31992226","title":"NFкB is a critical transcriptional regulator of atypical cadherin FAT1 in glioma.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31992226","citation_count":17,"is_preprint":false},{"pmid":"28972610","id":"PMC_28972610","title":"fat-1 mice prevent high-fat plus high-sugar diet-induced non-alcoholic fatty liver disease.","date":"2017","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/28972610","citation_count":17,"is_preprint":false},{"pmid":"26721716","id":"PMC_26721716","title":"Loss of FAT1 during the progression from DCIS to IDC and predict poor clinical outcome in breast cancer.","date":"2015","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26721716","citation_count":17,"is_preprint":false},{"pmid":"30588551","id":"PMC_30588551","title":"A Novel Dietary Source of EPA and DHA: Metabolic Engineering of an Important Freshwater Species-Common Carp by fat1-Transgenesis.","date":"2018","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30588551","citation_count":17,"is_preprint":false},{"pmid":"33109851","id":"PMC_33109851","title":"IDH1-R132H Suppresses Glioblastoma Malignancy through FAT1-ROS-HIF-1α Signaling.","date":"2020","source":"Neurology India","url":"https://pubmed.ncbi.nlm.nih.gov/33109851","citation_count":16,"is_preprint":false},{"pmid":"34390292","id":"PMC_34390292","title":"Fat1 suppresses the tumor-initiating ability of nonsmall cell lung cancer cells by promoting Yes-associated protein 1 nuclear-cytoplasmic translocation.","date":"2021","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34390292","citation_count":15,"is_preprint":false},{"pmid":"20725110","id":"PMC_20725110","title":"Fat-1 gene modulates the fatty acid composition of femoral and vertebral phospholipids.","date":"2010","source":"Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/20725110","citation_count":15,"is_preprint":false},{"pmid":"33665922","id":"PMC_33665922","title":"Fat-1 transgenic mice rich in endogenous omega-3 fatty acids are protected from lipopolysaccharide-induced cardiac dysfunction.","date":"2021","source":"ESC heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/33665922","citation_count":15,"is_preprint":false},{"pmid":"27658533","id":"PMC_27658533","title":"Mitigation of indomethacin-induced gastrointestinal damages in fat-1 transgenic mice via gate-keeper action of ω-3-polyunsaturated fatty acids.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27658533","citation_count":15,"is_preprint":false},{"pmid":"34712552","id":"PMC_34712552","title":"FAT1 and PTPN14 Regulate the Malignant Progression and Chemotherapy Resistance of Esophageal Cancer through the Hippo Signaling Pathway.","date":"2021","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/34712552","citation_count":14,"is_preprint":false},{"pmid":"32233593","id":"PMC_32233593","title":"miR-223-3p regulating the occurrence and development of liver cancer cells by targeting FAT1 gene.","date":"2019","source":"Mathematical biosciences and engineering : MBE","url":"https://pubmed.ncbi.nlm.nih.gov/32233593","citation_count":14,"is_preprint":false},{"pmid":"35034245","id":"PMC_35034245","title":"Circ-FAT1 Up-Regulates FOSL2 Expression by Sponging miR-619-5p to Facilitate Colorectal Cancer Progression.","date":"2022","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35034245","citation_count":13,"is_preprint":false},{"pmid":"32705150","id":"PMC_32705150","title":"Sulforaphane suppresses the viability and metastasis, and promotes the apoptosis of bladder cancer cells by inhibiting the expression of FAT‑1.","date":"2020","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32705150","citation_count":13,"is_preprint":false},{"pmid":"34013115","id":"PMC_34013115","title":"Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling.","date":"2021","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/34013115","citation_count":13,"is_preprint":false},{"pmid":"24012777","id":"PMC_24012777","title":"n-3 polyunsaturated fatty acids and HER2-positive breast cancer: interest of the fat-1 transgenic mouse model over conventional dietary supplementation.","date":"2013","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/24012777","citation_count":13,"is_preprint":false},{"pmid":"17294369","id":"PMC_17294369","title":"The expression of Fat-1 cadherin during chick limb development.","date":"2007","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17294369","citation_count":12,"is_preprint":false},{"pmid":"28158319","id":"PMC_28158319","title":"DNMT 1 maintains hypermethylation of CAG promoter specific region and prevents expression of exogenous gene in fat-1 transgenic sheep.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28158319","citation_count":12,"is_preprint":false},{"pmid":"38986165","id":"PMC_38986165","title":"FAT1 as a tumor mutation burden specific gene affects the immunotherapy effect in head and neck squamous cell cancer.","date":"2024","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/38986165","citation_count":11,"is_preprint":false},{"pmid":"26114487","id":"PMC_26114487","title":"Atypical Cadherin Fat1 Is Required for Lens Epithelial Cell Polarity and Proliferation but Not for Fiber Differentiation.","date":"2015","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/26114487","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54345,"output_tokens":7735,"usd":0.13953,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17517,"output_tokens":8210,"usd":0.146418,"stage2_stop_reason":"end_turn"},"total_usd":0.285948,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"FAT1 directly interacts with Ena/VASP proteins at the leading edge of lamellipodia, filopodia, and microspike tips; when the FAT1 cytoplasmic domain is targeted to mitochondrial outer leaflets it recruits actin polymerization machinery and induces ectopic actin polymerization; FAT1 knockdown decreases VASP recruitment to the leading edge, impairs lamellipodial dynamics, and attenuates cell migration, establishing FAT1 as a proximal regulator of Ena/VASP-dependent cytoskeletal dynamics.\",\n      \"method\": \"Co-immunoprecipitation, ectopic targeting/recruitment assay, siRNA knockdown, wound-healing migration assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding shown, ectopic domain recruitment reconstituted, knockdown phenotype with specific molecular readout; replicated conceptually in a companion paper (PMID:15148305)\",\n      \"pmids\": [\"15343270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian Fat1 localizes to filopodial tips, lamellipodial edges, and cell-cell boundaries overlapping with dynamic actin structures; RNAi-mediated knockdown disorganizes junction-associated F-actin and actin cables, disturbs cell-cell contacts, and inhibits cell polarity at wound margins; Ena/VASP proteins were identified as downstream effectors.\",\n      \"method\": \"RNAi knockdown, immunofluorescence localization, actin cytoskeleton imaging, wound-healing assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined cellular phenotype, direct localization, Ena/VASP identified as effector; corroborated by PMID:15343270\",\n      \"pmids\": [\"15148305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The FAT1 cytoplasmic domain contains a nuclear localization signal and undergoes proteolytic processing: first the extracellular domain is cleaved, then the resulting transmembrane fragment is released to the cytosol and translocates to the nucleus, indicating regulated intramembrane proteolysis governs FAT1 intracellular signaling.\",\n      \"method\": \"EGFP fusion constructs expressed in HEK293/HeLa cells, subcellular fractionation, deletion mutagenesis of NLS\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional domain mapping, single lab, multiple constructs\",\n      \"pmids\": [\"15922730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Fat1 intracellular domain interacts with β-catenin, inhibiting β-catenin nuclear localization and transcriptional activity; Fat1 itself undergoes cleavage generating intracellular fragments that localize to the nucleus; Fat1 knockdown enhances cyclin D1 expression and VSMC proliferation while reducing migration, establishing a dual anti-proliferative/pro-migratory role in vascular smooth muscle cells.\",\n      \"method\": \"Co-immunoprecipitation, β-catenin reporter assay, siRNA knockdown, cyclin D1 promoter assay, migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, reporter assay, KD phenotype with defined molecular pathway; multiple orthogonal methods in one study\",\n      \"pmids\": [\"16682528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Three novel splice isoforms of FAT1 were identified; only wild-type FAT1 localizes to the cellular leading edge via a phosphotyrosine-binding-like (DN_XYH) motif disrupted by peptide inserts in alternative isoforms; spliced isoforms localize exclusively to intercellular junctions; overexpression of FAT1(WT) induces cellular protrusions and knockdown of spliced isoforms increases wound healing, demonstrating that differential subcellular distribution of isoforms controls migratory behavior.\",\n      \"method\": \"Isoform cloning, domain mutagenesis, subcellular immunofluorescence, overexpression, siRNA knockdown, wound-healing assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of targeting motif, isoform-specific KD/OE, multiple orthogonal localization and functional readouts in one study\",\n      \"pmids\": [\"17500054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fat1 physically interacts with Atrophin proteins (Atr1 and Atr2); interaction requires Fat1 amino acids 4300–4400 and an intact Atro-box in Atrophins; Fat1 and Atrs co-localize at cell-cell junctions, perinuclear area, and nucleus in VSMCs; Atr1 and Atr2L have opposing effects on VSMC directional migration, and the migration-enhancing effect of Atr2L knockdown requires Fat1 expression, placing Fat1 upstream of Atrophin-mediated polarity.\",\n      \"method\": \"Co-immunoprecipitation with domain-mapping, siRNA knockdown, immunocytochemistry, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, epistasis via KD rescue, defined cellular phenotype\",\n      \"pmids\": [\"19131340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human FAT1 undergoes dual proteolytic processing: furin-dependent cleavage into a non-covalent heterodimer (required for normal cell-surface expression) and, in melanoma cells, furin-independent cleavage generating a persistent 65-kDa membrane-bound cytoplasmic fragment; the uncleaved proform is additionally expressed at the melanoma cell surface; differences in processing produce distinct subcellular distributions—cell-cell junctional in keratinocytes vs. cytosolic in melanoma.\",\n      \"method\": \"Northern blot, protein inhibitor studies (furin inhibitor), Western blot, immunofluorescence/confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization of processing, inhibitor and localization data, single lab\",\n      \"pmids\": [\"21680732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FAT1 binds β-catenin and antagonizes its nuclear localization; somatic FAT1 loss-of-function mutations in glioblastoma, colorectal, and head/neck cancers promote Wnt signaling and tumorigenesis; FAT1 suppresses cancer cell growth in vitro and in vivo, identifying it as a 4q35 tumor suppressor that controls aberrant Wnt activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro growth assay, xenograft in vivo model, somatic mutation analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating β-catenin binding, in vitro and in vivo functional loss-of-function, replicated across multiple cancer types\",\n      \"pmids\": [\"23354438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Constitutive inactivation of Fat1 in mice uncouples individual myoblast polarity within migrating chains, altering the shape of specific shoulder and face muscles; tissue-specific ablation via Pax3-cre reproduces muscle shape defects in limb but not face muscles, demonstrating a cell-autonomous role of Fat1 in migrating muscle precursor polarity.\",\n      \"method\": \"Constitutive and conditional (Pax3-cre) knockout mouse models, histological and morphological analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic ablation, defined polarity phenotype, cell-autonomous epistasis established\",\n      \"pmids\": [\"23785297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FAT1 knockdown in high-grade glioma cells increases expression of the tumor suppressor PDCD4, which then inhibits AP-1 transcription by blocking c-Jun phosphorylation, reducing expression of AP-1 target genes (MMP3, VEGF-C, PLAU) and pro-inflammatory regulators (COX-2, IL-1β, IL-6); simultaneous silencing of PDCD4 and FAT1 reverses these effects, establishing FAT1 as an upstream regulator of the PDCD4–AP-1 inflammatory axis.\",\n      \"method\": \"siRNA knockdown (FAT1 alone and dual FAT1/PDCD4), gene expression analysis, reporter assay, migration/invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by dual KD rescue, multiple target gene readouts, single lab\",\n      \"pmids\": [\"22986533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FAT1 interacts with caspase-8, preventing caspase-8 association with the death-inducing signaling complex (DISC); FAT1 knockdown or CRISPR/Cas9 knockout sensitizes glioblastoma cells to death receptor-mediated apoptosis by enhancing procaspase-8 recruitment to the DISC and increasing formation of caspase-8-containing secondary signaling complexes.\",\n      \"method\": \"Genome-wide siRNA synthetic lethal screen, Co-immunoprecipitation of FAT1–caspase-8 complex, CRISPR/Cas9 knockout, DISC immunoprecipitation, apoptosis assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide screen, Co-IP of specific complex, CRISPR KO validation, mechanistic DISC recruitment readout\",\n      \"pmids\": [\"24442637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM10 mediates ectodomain shedding of Fat1 from pancreatic cancer cells, releasing a soluble extracellular fragment into the secretome; chemical inhibition and siRNA knockdown of ADAM10 reduce Fat1 shedding; the shed ectodomain is detectable in serum of pancreatic cancer patients.\",\n      \"method\": \"Mass spectrometry, Western blot, ADAM10 chemical inhibitor and siRNA knockdown, ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sheddase identified by KD and inhibitor, biochemical characterization of fragments, single lab\",\n      \"pmids\": [\"24625754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FAT1 acts upstream of the Hippo pathway to activate core Hippo kinase components and antagonize TAZ; FAT1 silencing promotes nuclear-cytoplasmic shuttling of TAZ, leading to enhanced CTGF transcription and increased nuclear Smad3; TAZ knockdown reverses the effects of FAT1 depletion, connecting FAT1 to TAZ–TGF-β signaling and placing FAT1 as an upstream Hippo regulator during neuronal differentiation.\",\n      \"method\": \"Gene silencing, Hippo kinase activity assay, subcellular fractionation, reporter assay, epistasis by double KD\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double KD, multiple pathway readouts, single lab\",\n      \"pmids\": [\"26104008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fat1 interacts genetically and physically with Fat4 to regulate neural tube closure, cortical precursor proliferation, and apical constriction in mouse brain; proteomic analysis shows Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins; in vitro data indicate Fat1 and Fat4 form cis-heterodimers, providing a mechanism for co-ordinating distinct downstream actin and junctional pathways.\",\n      \"method\": \"Genetic epistasis (double knockout mouse), proteomic co-precipitation, in vitro cis-heterodimer assay, in utero electroporation KD\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in double-KO mice, proteomics identifying distinct interactomes, in vitro heterodimer formation, multiple orthogonal methods\",\n      \"pmids\": [\"26209645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fat1 fragments accumulate in VSMC mitochondria and the Fat1 intracellular domain interacts with multiple inner mitochondrial membrane proteins; SMCs lacking Fat1 consume more oxygen for ATP production, contain more aspartate, and grow faster; a mitochondria-targeted Fat1 intracellular domain largely normalizes oxygen consumption; Fat1 deletion increases activity of respiratory complexes I and II and promotes complex-I-containing supercomplex formation; inactivation of SMC Fat1 in mice potentiates vascular injury response with increased medial hyperplasia.\",\n      \"method\": \"Mitochondrial fractionation, Co-IP with mitochondrial proteins, oxygen consumption measurement, metabolomics (aspartate), mitochondria-targeted domain rescue, respiratory complex activity assay, blue-native PAGE for supercomplexes, mouse vascular injury model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted mitochondrial interaction, domain-targeted rescue, multiple orthogonal biochemical and in vivo methods, published in Nature\",\n      \"pmids\": [\"27828948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAT1 loss-of-function in glioma cells reduces HIF-1α expression under hypoxia by compromising EGFR-Akt signaling and increasing VHL-dependent proteasomal degradation of HIF-1α; FAT1 knockdown also reduces downstream HIF-1α target gene expression (CA9, GLUT1, VEGFA, etc.) and decreases GBM cell invasiveness, establishing FAT1 as an upstream regulator of HIF-1α stability.\",\n      \"method\": \"siRNA knockdown, EGFR-Akt pathway analysis, proteasomal degradation assay, invasion assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism dissected via pathway inhibitors and KD, single lab\",\n      \"pmids\": [\"27536856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAT1 loss-of-function in podocytes leads to decreased cell adhesion and migration, partially reversed by a RAC1/CDC42 activator; podocyte-specific Fat1 deletion in mice induces abnormal glomerular filtration barrier development with foot process effacement; knockdown in renal tubular cells reduces active RAC1 and CDC42 and causes lumen formation defects; fat1 knockdown in zebrafish causes pronephric cysts rescued by RAC1/CDC42 activators, placing FAT1 upstream of RAC1/CDC42 in podocyte and tubular function.\",\n      \"method\": \"Patient mutation analysis, fibroblast/podocyte adhesion/migration assay, RAC1/CDC42 activation assay, conditional knockout mouse, zebrafish morpholino knockdown with pharmacological rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (human cells, mouse KO, zebrafish), pharmacological epistasis, defined molecular pathway\",\n      \"pmids\": [\"26905694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAT1 assembles a multimeric Hippo signaling complex (signalome) that enables activation of core Hippo kinases (MST/LATS) by TAOKs, resulting in YAP1 inactivation; FAT1 functional loss in HNSCC causes YAP1 activation that acts as an oncogenic driver; this establishes FAT1 as a scaffold that couples upstream TAOK kinases to the canonical Hippo kinase cascade.\",\n      \"method\": \"Pancancer genomic analysis, Co-IP/complex assembly assay, kinase activity assay, YAP1 reporter assay, FAT1 loss-of-function in HNSCC cells and mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — signalome complex biochemically assembled, kinase activation measured, multiple cancer models, published in Nature Communications\",\n      \"pmids\": [\"29985391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAT1 loss leads to YAP/TAZ accumulation on the CDK6 promoter, driving CDK6 upregulation via the Hippo pathway; suppression of CDK6 in FAT1-deficient ER+ breast cancer cells restores sensitivity to CDK4/6 inhibitors; genomic alterations in other Hippo components also promote CDK4/6i resistance, placing FAT1 loss upstream of the YAP/TAZ–CDK6 axis of drug resistance.\",\n      \"method\": \"Genomic analysis of patient tumors, ChIP demonstrating YAP/TAZ occupancy on CDK6 promoter, CDK6 suppression rescue experiment\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP evidence for transcription factor occupancy, rescue experiment, genomic data from patient cohort corroborating mechanism\",\n      \"pmids\": [\"30537512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tissue-specific Fat1 ablation in mesenchyme-derived connective tissue non-cell-autonomously controls cutaneous maximus muscle progenitor spreading, myogenic differentiation, and motor innervation; Fat1 ablation in motor neurons impairs axonal growth and motor pool specification, indirectly affecting muscle progenitor progression; these tissue-specific roles demonstrate Fat1 coordinates neuromuscular morphogenesis through complementary activities in distinct cell types.\",\n      \"method\": \"Tissue-specific conditional Cre knockout (mesenchyme-Fat1, neuron-Fat1), histological and molecular phenotyping\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic ablation with defined cell-autonomous and non-cell-autonomous phenotypic readouts\",\n      \"pmids\": [\"29768404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAT1 loss activates a CAMK2–CD44–SRC axis promoting YAP1 nuclear translocation and ZEB1 expression (mesenchymal state), while also inactivating EZH2 to promote SOX2 expression (epithelial state), resulting in a hybrid EMT state with increased tumor stemness and metastasis; these mechanisms were established by transcriptional/chromatin profiling and proteomic analyses combined with mechanistic studies in mouse models of skin SCC.\",\n      \"method\": \"Mouse genetic deletion models (skin SCC), transcriptional profiling, chromatin profiling, proteomics, mechanistic pathway analysis (CAMK2/CD44/SRC/YAP1/EZH2)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal omics approaches plus mechanistic validation in mouse models, published in Nature\",\n      \"pmids\": [\"33328637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Angiotensin II increases Fat1 mRNA and protein expression and promotes Fat1 translocation to the cell membrane via AT1R–ERK1/2–Nox1-derived ROS signaling; Nox1 siRNA inhibits Ang II-induced Fat1 protein expression; Fat1 knockdown inhibits Ang II-induced VSMC migration, establishing Fat1 as a downstream mediator of Ang II/Nox1/ERK1/2 signaling in VSMC migration.\",\n      \"method\": \"siRNA knockdown (Nox1 and Fat1), AT1R antagonist, antioxidant treatment, ERK1/2 inhibitor, ROS measurement, migration assay (Boyden chamber)\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic inhibitors delineating pathway, single lab\",\n      \"pmids\": [\"24445059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAT1 knockdown in ESCC cells enhances cisplatin resistance and stemness via Wnt/β-catenin signaling: FAT1 loss induces nuclear translocation of β-catenin, which binds to the ABCC3 promoter (by ChIP) and drives ABCC3 expression, increasing drug efflux; β-catenin inhibition reverses FAT1-KD-mediated ABCC3 upregulation.\",\n      \"method\": \"siRNA knockdown, sphere-forming assay, drug efflux assay, ChIP (β-catenin on ABCC3 promoter), Western blot\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly linking β-catenin to ABCC3 promoter downstream of FAT1, single lab\",\n      \"pmids\": [\"35606602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Endothelial FAT1 promotes degradation of YAP/TAZ by recruiting the E3 ubiquitin ligase Mind Bomb-2 (MIB2); FAT1 interacts with MIB2 (identified by Co-IP), and this interaction mediates FAT1-induced YAP/TAZ ubiquitination; loss of endothelial FAT1 or MIB2 increases YAP/TAZ protein levels and canonical target gene expression, leading to increased endothelial proliferation and angiogenesis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (FAT1–MIB2), ubiquitination assay, endothelial-specific KO mouse models, angiogenesis models in vitro and in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying specific E3 ligase, ubiquitination assay, in vivo KO recapitulates FAT1-depletion phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"37031213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAT1 mutations in patient-derived urinary renal epithelial cells are associated with decreased phosphorylation of MST kinase and YAP, and transcriptional upregulation of YAP target genes, linking FAT1 loss to deregulation of Hippo signaling in renal disease.\",\n      \"method\": \"Immunoblotting of patient urinary epithelial cells (qPCR and Western blot for Hippo pathway components), genetic characterization\",\n      \"journal\": \"Kidney international reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — patient-derived primary cells, pathway readout but no reconstitution or rescue experiment; replicated across multiple patients\",\n      \"pmids\": [\"34013115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NF-κB (RelA/p65) directly binds a motif at –90 to –80 bp of the FAT1 promoter and drives FAT1 transcription in GBM cells; this was shown by promoter deletion constructs, site-directed mutagenesis of the NF-κB motif abolishing reporter activity, and ChIP confirming endogenous NF-κB occupancy; NF-κB activators (hypoxia, TNF-α, ectopic NF-κB) increase FAT1 expression, and NF-κB siRNA decreases it.\",\n      \"method\": \"Promoter deletion/reporter assay, site-directed mutagenesis, ChIP, siRNA knockdown, NF-κB activator treatments\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis + ChIP confirming direct binding, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31992226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"E2F1 occupies the FAT1 promoter and transcriptionally activates FAT1 expression; E2F1 depletion decreases FAT1 mRNA and transcriptional activity as shown by ChIP and luciferase reporter assays in ESCC cells.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown of E2F1\",\n      \"journal\": \"Chinese journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay, single lab\",\n      \"pmids\": [\"31564804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPC3 (glypican-3) interacts with FAT1 on liver cancer cell surfaces; the GPC3-binding region was mapped to FAT1 residues 4013–4181 (last four EGF-like domains) by ELISA and flow cytometry; GPC3 and FAT1 co-regulate EMT-related genes (Snail, Vimentin, E-Cadherin) and HCC cell migration.\",\n      \"method\": \"Co-immunoprecipitation/binding assay, ELISA domain mapping, flow cytometry, migration assay, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped binding interaction, functional co-regulation, single lab\",\n      \"pmids\": [\"33420124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAT1 is identified as the target antigen in hematopoietic stem cell transplant-associated membranous nephropathy; laser microdissection/tandem mass spectrometry detected FAT1 protein deposits in glomerular basement membranes; anti-FAT1 IgG and IgG4 antibodies were detected in serum and kidney eluates of affected patients but not in PLA2R-MN controls, establishing FAT1 as an immune target in this disease.\",\n      \"method\": \"Laser microdissection and tandem mass spectrometry (MS/MS), immunohistochemistry/immunofluorescence, Western blot with eluated antibodies from kidney biopsies\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS/MS antigen identification replicated in discovery + validation cohort, antibody binding confirmed biochemically\",\n      \"pmids\": [\"35321939\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAT1 is a giant atypical protocadherin that functions as a context-dependent tumor suppressor and signaling scaffold: at the cell periphery it directly binds Ena/VASP proteins to regulate actin polymerization and directed cell migration; its intracellular domain interacts with β-catenin to suppress Wnt/nuclear β-catenin signaling; it assembles a multimeric Hippo signalome (incorporating TAOK kinases and core MST/LATS kinases) to restrain YAP/TAZ activity, with YAP/TAZ degradation further enforced through FAT1-recruited E3 ligase MIB2-mediated ubiquitination; FAT1 fragments translocate to mitochondria where they interact with respiratory complex proteins to brake mitochondrial respiration and limit cell growth; FAT1 also interacts with Atrophin proteins to control cell polarity and with caspase-8 to prevent its recruitment to the DISC, thereby modulating extrinsic apoptosis; NF-κB and E2F1 transcriptionally activate FAT1 expression, and its ectodomain is shed by ADAM10; loss of FAT1 activates a CAMK2–CD44–SRC–YAP1 axis driving hybrid EMT and tumor stemness, while its intracellular domain can shuttle to the nucleus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAT1 is a giant atypical protocadherin that operates as a context-dependent tumor suppressor and membrane-anchored signaling scaffold, coupling cell-surface adhesion to cytoskeletal, transcriptional, and metabolic control [#7, #17]. At the cell periphery, FAT1 localizes to lamellipodial edges, filopodial tips, and cell-cell junctions, where it directly binds Ena/VASP proteins to drive actin polymerization, lamellipodial dynamics, and directed migration; isoform-specific use of a leading-edge targeting motif partitions FAT1 between migratory and junctional pools [#0, #1, #4]. FAT1 is processed by regulated proteolysis—furin-dependent maturation into a cell-surface heterodimer and release of an intracellular fragment bearing a nuclear localization signal—and its ectodomain is shed by ADAM10 [#2, #6, #11]. The released intracellular domain binds β-catenin to restrain its nuclear translocation and transcriptional output, so that FAT1 loss-of-function in glioblastoma, colorectal, head/neck, and esophageal cancers activates Wnt signaling and promotes growth, stemness, and drug efflux via a β-catenin–ABCC3 axis [#3, #7, #22]. In parallel, FAT1 assembles a multimeric Hippo signalome that couples TAOK kinases to the MST/LATS cascade, holding YAP/TAZ inactive; endothelial FAT1 additionally recruits the E3 ligase MIB2 to ubiquitinate and degrade YAP/TAZ, and FAT1 loss drives YAP/TAZ-dependent CDK6 induction, angiogenesis, and a CAMK2–CD44–SRC–YAP1 hybrid-EMT/stemness program [#12, #17, #18, #20, #23]. FAT1 intracellular fragments also localize to mitochondria, where the cytoplasmic domain binds inner-membrane respiratory proteins to limit oxygen consumption, respiratory complex activity, and cell growth [#14]. Through GTPase regulation (RAC1/CDC42), FAT1 controls polarity and morphogenesis in podocytes, renal tubules, migrating myoblasts, and the neuromuscular system, and it interacts with Atrophin proteins and forms cis-heterodimers with Fat4 to coordinate junctional and actin-regulating pathways [#5, #8, #13, #16, #19]. FAT1 also restrains extrinsic apoptosis by sequestering caspase-8 from the DISC, and its expression is transcriptionally driven by NF-κB and E2F1 [#10, #25, #26]. FAT1 is an autoantigen in hematopoietic stem cell transplant-associated membranous nephropathy [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established FAT1's first molecular activity—linking a giant cadherin directly to actin dynamics by showing it binds and recruits Ena/VASP proteins at the leading edge to control migration.\",\n      \"evidence\": \"Co-IP, ectopic mitochondrial-targeting recruitment assay, siRNA knockdown and wound-healing in mammalian cells\",\n      \"pmids\": [\"15343270\", \"15148305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how FAT1 ligand engagement at the surface triggers Ena/VASP recruitment\", \"No structural detail of the FAT1–Ena/VASP interface\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that FAT1 signals via regulated intramembrane proteolysis, releasing an NLS-bearing intracellular fragment to the nucleus, providing the mechanistic basis for downstream transcriptional control.\",\n      \"evidence\": \"EGFP-fusion constructs, subcellular fractionation, and NLS deletion mutagenesis in HEK293/HeLa\",\n      \"pmids\": [\"15922730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease(s) responsible for intracellular cleavage not identified\", \"Endogenous nuclear function of the fragment not demonstrated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified β-catenin as a FAT1 intracellular partner, defining how FAT1 antagonizes Wnt/nuclear β-catenin signaling and balances proliferation against migration.\",\n      \"evidence\": \"Reciprocal Co-IP, β-catenin and cyclin D1 reporter assays, siRNA knockdown in vascular smooth muscle cells\",\n      \"pmids\": [\"16682528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether nuclear FAT1 fragment or membrane FAT1 mediates β-catenin sequestration\", \"Generality beyond VSMCs untested at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Explained how alternative splicing partitions FAT1 function, with a phosphotyrosine-binding-like motif directing wild-type FAT1 to the leading edge versus junctions for spliced isoforms.\",\n      \"evidence\": \"Isoform cloning, targeting-motif mutagenesis, isoform-specific knockdown/overexpression and wound-healing\",\n      \"pmids\": [\"17500054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue/context regulation of isoform choice not defined\", \"Binding partner of the DN_XYH motif not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed FAT1 upstream of Atrophin-mediated polarity by mapping a direct FAT1–Atrophin interaction and showing Atrophin migration effects require FAT1.\",\n      \"evidence\": \"Domain-mapped reciprocal Co-IP, siRNA epistasis, and migration assays in VSMCs\",\n      \"pmids\": [\"19131340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets of FAT1–Atrophin complex not defined\", \"Opposing Atr1/Atr2 effects mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Characterized FAT1 maturation, showing furin-dependent heterodimer formation for surface expression versus aberrant furin-independent processing in melanoma that alters subcellular distribution.\",\n      \"evidence\": \"Furin inhibitor studies, Western blot, and confocal localization in keratinocytes and melanoma cells\",\n      \"pmids\": [\"21680732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of melanoma-specific cytoplasmic fragment not tested\", \"Single-lab biochemical characterization\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined FAT1 as a recurrently mutated 4q35 tumor suppressor that restrains Wnt/β-catenin-driven tumorigenesis across multiple cancers.\",\n      \"evidence\": \"Co-IP, in vitro growth and xenograft assays, and somatic mutation analysis in glioblastoma, colorectal, and head/neck cancers\",\n      \"pmids\": [\"23354438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet integrate Wnt control with Hippo or other FAT1 pathways\", \"Mechanism of mutation-driven loss of β-catenin antagonism not structurally resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a cell-autonomous role for Fat1 in polarity of migrating muscle precursors, extending FAT1 polarity function to developmental morphogenesis in vivo.\",\n      \"evidence\": \"Constitutive and Pax3-cre conditional knockout mice with morphological muscle analysis\",\n      \"pmids\": [\"23785297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector linking Fat1 to myoblast polarity in vivo not defined\", \"Differential limb vs face dependence unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected FAT1 to an inflammatory transcription axis by showing FAT1 loss derepresses PDCD4 to suppress AP-1 target and pro-inflammatory gene expression in glioma.\",\n      \"evidence\": \"Single and dual FAT1/PDCD4 siRNA knockdown, reporter and gene-expression analysis, invasion assays\",\n      \"pmids\": [\"22986533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between FAT1 and PDCD4 regulation unresolved\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed an apoptosis-modulating role: FAT1 sequesters caspase-8 from the DISC, so FAT1 loss sensitizes cells to death-receptor apoptosis.\",\n      \"evidence\": \"Genome-wide synthetic-lethal siRNA screen, Co-IP, CRISPR knockout, and DISC immunoprecipitation in glioblastoma\",\n      \"pmids\": [\"24442637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FAT1–caspase-8 sequestration not defined\", \"Whether membrane or fragment FAT1 mediates this is unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified ADAM10 as the FAT1 sheddase, defining ectodomain release as a regulated event detectable as a circulating fragment.\",\n      \"evidence\": \"Mass spectrometry of secretome, ADAM10 inhibitor and siRNA, ELISA on patient serum\",\n      \"pmids\": [\"24625754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of shed ectodomain not demonstrated\", \"Link between shedding and intracellular signaling not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed Fat1 downstream of Ang II/Nox1/ERK signaling, showing it is both transcriptionally induced and membrane-translocated to mediate VSMC migration.\",\n      \"evidence\": \"Nox1/Fat1 siRNA, AT1R antagonist, ERK inhibitor, ROS measurement, Boyden-chamber migration\",\n      \"pmids\": [\"24445059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of signal-induced membrane translocation not defined\", \"Single lab pharmacological dissection\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"First positioned FAT1 upstream of the Hippo pathway, activating core kinases to antagonize TAZ and its TGF-β/Smad3 crosstalk during neuronal differentiation.\",\n      \"evidence\": \"Gene silencing, Hippo kinase activity assay, fractionation, reporter assays, and double-knockdown epistasis\",\n      \"pmids\": [\"26104008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not yet identify the scaffold mechanism coupling FAT1 to Hippo kinases\", \"Single lab, single differentiation context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed Fat1 and Fat4 form cis-heterodimers and bind distinct actin/junctional interactomes to coordinate neural tube closure and cortical morphogenesis.\",\n      \"evidence\": \"Double-knockout mouse genetics, proteomic co-precipitation, in vitro heterodimer assay, in utero electroporation\",\n      \"pmids\": [\"26209645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of each interactome to specific phenotypes not separated\", \"Structural basis of cis-heterodimerization unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a metabolic function: FAT1 fragments enter mitochondria and bind respiratory proteins to brake oxidative phosphorylation and limit growth.\",\n      \"evidence\": \"Mitochondrial fractionation, Co-IP, oxygen consumption, metabolomics, mitochondria-targeted domain rescue, blue-native PAGE, and vascular injury mouse model\",\n      \"pmids\": [\"27828948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FAT1 fragments are routed to mitochondria not defined\", \"Identity of the rate-limiting respiratory targets incompletely mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected FAT1 to hypoxic signaling, showing FAT1 sustains HIF-1α via EGFR-Akt and protects it from VHL-dependent degradation in glioma.\",\n      \"evidence\": \"siRNA knockdown, EGFR-Akt pathway and proteasomal degradation analysis, invasion assays\",\n      \"pmids\": [\"27536856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking FAT1 to EGFR-Akt not defined\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established FAT1 as an upstream RAC1/CDC42 regulator required for podocyte and tubular adhesion, migration, and lumen/barrier morphogenesis.\",\n      \"evidence\": \"Patient mutations, adhesion/migration assays, RAC1/CDC42 activation assays, conditional knockout mice, zebrafish knockdown with pharmacological rescue\",\n      \"pmids\": [\"26905694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effector linking FAT1 to RAC1/CDC42 activation not identified\", \"Relationship to FAT1's Ena/VASP cytoskeletal arm unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the FAT1–Hippo mechanism by showing FAT1 assembles a signalome scaffold coupling TAOK kinases to MST/LATS to inactivate YAP1, with loss acting as an oncogenic driver.\",\n      \"evidence\": \"Pan-cancer genomics, Co-IP/complex assembly, kinase and YAP1 reporter assays, FAT1 loss in HNSCC cells and mouse models\",\n      \"pmids\": [\"29985391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the signalome not defined\", \"Trigger that nucleates assembly at the membrane unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked FAT1 loss to therapy resistance via the Hippo–YAP/TAZ–CDK6 axis, explaining CDK4/6 inhibitor resistance in ER+ breast cancer.\",\n      \"evidence\": \"Patient genomics, ChIP for YAP/TAZ on the CDK6 promoter, and CDK6 suppression rescue\",\n      \"pmids\": [\"30537512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FAT1 directly or indirectly sets CDK6 promoter occupancy not separated\", \"Generalizability beyond ER+ breast cancer untested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated cell-autonomous and non-cell-autonomous Fat1 roles coordinating muscle progenitor spreading, differentiation, and motor innervation across mesenchyme and neurons.\",\n      \"evidence\": \"Tissue-specific conditional Cre knockouts with histological and molecular phenotyping\",\n      \"pmids\": [\"29768404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal mediating non-cell-autonomous control of progenitors not identified\", \"Molecular link to FAT1 polarity machinery not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified E2F1 as a transcriptional activator of FAT1, adding cell-cycle-coupled control of FAT1 expression.\",\n      \"evidence\": \"ChIP, luciferase reporter, and E2F1 siRNA in ESCC cells\",\n      \"pmids\": [\"31564804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions driving E2F1-dependent FAT1 induction not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Integrated FAT1 loss into a hybrid-EMT/stemness program through a CAMK2–CD44–SRC–YAP1 axis and EZH2 inactivation, explaining its pro-metastatic effects on tumor plasticity.\",\n      \"evidence\": \"Skin SCC mouse genetic models with transcriptional, chromatin, and proteomic profiling and pathway validation\",\n      \"pmids\": [\"33328637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FAT1 normally restrains CAMK2 activation not defined\", \"Relative contributions of the epithelial vs mesenchymal arms to metastasis unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified NF-κB (RelA/p65) as a direct transcriptional activator of FAT1, linking inflammatory/hypoxic stimuli to FAT1 expression in glioblastoma.\",\n      \"evidence\": \"Promoter deletion/mutagenesis, ChIP, siRNA knockdown, and NF-κB activator treatments\",\n      \"pmids\": [\"31992226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of NF-κB-driven FAT1 induction for tumor behavior not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed in patient cells that FAT1 mutation deregulates Hippo signaling, with reduced MST/YAP phosphorylation and YAP target upregulation in renal disease.\",\n      \"evidence\": \"Immunoblotting and qPCR of patient-derived urinary renal epithelial cells\",\n      \"pmids\": [\"34013115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution or rescue to prove causality\", \"Patient-derived correlative data only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a direct FAT1–GPC3 surface interaction co-regulating EMT genes and migration in liver cancer, identifying a cell-surface FAT1 ligand partner.\",\n      \"evidence\": \"Binding/Co-IP, ELISA domain mapping, flow cytometry, and migration/gene-expression assays in HCC cells\",\n      \"pmids\": [\"33420124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPC3 binding alters FAT1 intracellular signaling not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established FAT1 as a disease autoantigen in hematopoietic stem cell transplant-associated membranous nephropathy.\",\n      \"evidence\": \"Laser microdissection MS/MS, immunostaining, and Western blot with eluted patient antibodies in discovery and validation cohorts\",\n      \"pmids\": [\"35321939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which anti-FAT1 antibodies cause glomerular injury not defined\", \"Trigger of FAT1 autoimmunity unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a FAT1-loss drug-resistance mechanism in esophageal cancer via β-catenin-driven ABCC3 transcription enhancing drug efflux and stemness.\",\n      \"evidence\": \"siRNA knockdown, sphere-forming and drug-efflux assays, and ChIP for β-catenin on the ABCC3 promoter\",\n      \"pmids\": [\"35606602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect FAT1 control of β-catenin promoter binding not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MIB2 as a FAT1-recruited E3 ligase that ubiquitinates and degrades YAP/TAZ, adding a degradation arm to FAT1's Hippo control in endothelial cells.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and endothelial-specific knockout mice with angiogenesis models\",\n      \"pmids\": [\"37031213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FAT1 recruits MIB2 to YAP/TAZ structurally unresolved\", \"Relationship to the FAT1–TAOK–MST/LATS kinase arm not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FAT1's distinct functional arms—Ena/VASP-driven actin dynamics, β-catenin/Wnt antagonism, Hippo signalome assembly with MIB2-mediated YAP/TAZ degradation, RAC1/CDC42-dependent polarity, mitochondrial respiratory braking, and caspase-8 sequestration—are coordinated by a single receptor and switched by proteolytic processing or ligand engagement.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural or stoichiometric model integrating FAT1's multiple intracellular complexes\", \"The signal/ligand that toggles between FAT1's signaling modes is undefined\", \"How processing-derived fragments are partitioned among nucleus, mitochondria, and membrane is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 17, 27]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [17, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6, 27]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 12, 17, 18, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 20, 28]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 13, 19, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"FAT1 Hippo signalome (TAOK–MST/LATS)\", \"death-inducing signaling complex (DISC, via caspase-8)\", \"Fat1–Fat4 cis-heterodimer\"],\n    \"partners\": [\"CTNNB1\", \"MIB2\", \"CASP8\", \"YAP1\", \"TAZ\", \"ATN1\", \"FAT4\", \"GPC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}