{"gene":"FRMD6","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2005,"finding":"FRMD6/Willin contains a recognizable FERM domain at its N-terminus, is capable of binding phospholipids, and can co-localize with actin at the plasma membrane. Plasma membrane localization is not influenced by cytochalasin D-induced actin disruption but is induced by the addition of epidermal growth factor.","method":"Immunofluorescence/co-localization, cytochalasin D treatment, EGF stimulation, phospholipid binding assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with pharmacological manipulation and functional stimulus, single lab, multiple assays","pmids":["16137681"],"is_preprint":false},{"year":2011,"finding":"Willin/FRMD6 activates the Hippo signaling pathway in mammalian cells: ectopic willin expression increases phosphorylation of MST1/2, LATS1, and YAP. This effect can be antagonized by ezrin. In MCF10A cells, willin overexpression antagonizes YAP activity via its N-terminal FERM domain. Loss of willin displays epithelial-to-mesenchymal transition features.","method":"Ectopic expression, Western blot for phosphorylated pathway components, FERM domain truncation constructs, knockdown with phenotypic readout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal domain mapping and phosphorylation assays, single lab, multiple orthogonal methods","pmids":["21666719"],"is_preprint":false},{"year":2011,"finding":"Willin/FRMD6 recruits aPKC and Par6 to the apical junctional complex (AJC) independently of Par3. Simultaneous depletion of Willin and Par3 removes aPKC/Par6 from AJCs and induces apical constriction via upregulation of AJC-associated ROCK levels. aPKC phosphorylates ROCK and suppresses its junctional localization, defining a Willin/Par3-aPKC-ROCK pathway controlling epithelial apical morphology.","method":"siRNA depletion (single and double knockdown), immunofluorescence, Western blot, genetic epistasis analysis in epithelial cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by double-KD rescue, reciprocal localization experiments, pathway ordering by multiple orthogonal methods, published in high-tier journal","pmids":["21685893"],"is_preprint":false},{"year":2012,"finding":"Willin/FRMD6 binds to nectins (Ig-family adhesion proteins) at the apical junctional complex, and this binding is required for junctional recruitment of Willin. Nectin positioning at the AJC depends on afadin binding, placing the nectin-afadin interaction upstream of Willin localization.","method":"Co-immunoprecipitation, immunofluorescence, knockdown of nectins and afadin with Willin localization readout","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP binding and localization experiments with functional consequence, single lab, two methods","pmids":["22512338"],"is_preprint":false},{"year":2013,"finding":"In mammalian sciatic nerve fibroblasts, Willin/FRMD6 is predominantly expressed and its expression activates the Hippo signaling cascade, inducing YAP translocation from nucleus to cytoplasm (Ser127 phosphorylation). Willin expression inhibits cellular proliferation but induces faster directional migration and increased expression of nerve regeneration factors.","method":"Expression analysis, Western blot for pYAP-Ser127, immunofluorescence for YAP localization, proliferation and migration assays (scratch assay)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — YAP subcellular localization with functional consequence, proliferation and migration phenotype, single lab, multiple assays","pmids":["23593160"],"is_preprint":false},{"year":2016,"finding":"FRMD6 inhibits activation of receptor tyrosine kinases c-Met and PDGFR and their downstream ERK and AKT kinases in glioblastoma cells. Increased FRMD6 expression displays little effect on the Hippo pathway in GBM cells (negative result for Hippo activation). Expression of constitutively active c-Met (TPR-Met) largely reverses the anti-GBM effect of FRMD6 in vivo, placing FRMD6 upstream of RTK activity.","method":"Overexpression and knockdown in GBM cell lines, Western blot for RTK/ERK/AKT phosphorylation, xenograft rescue with TPR-Met constitutively active construct","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo epistasis rescue experiment plus in vitro phosphorylation assays, single lab, multiple orthogonal methods","pmids":["27661120"],"is_preprint":false},{"year":2019,"finding":"In aged cardiac microvascular endothelial cells, BDNF-TrkB-T1 signaling recruits Willin/FRMD6 as a downstream effector to activate the Hippo pathway, which promotes cell migration. Willin acts downstream of TrkB-T1 in the BDNF-TrkB-T1-Willin-Hippo pathway.","method":"Co-immunoprecipitation/protein interaction, knockdown, cell migration assay, pathway epistasis in aged CMECs","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway epistasis established by knockdown with migration readout, receptor-effector interaction, single lab","pmids":["30667167"],"is_preprint":false},{"year":2020,"finding":"Willin/FRMD6 expression influences the mechanical phenotype and neuronal differentiation of SH-SY5Y neuronal cells by inversely regulating ERK1/2 pathway activity and downstream transcription factor NeuroD1. Changes in Willin/FRMD6 levels alter cell morphology, neurite-like extension formation, actin stress fiber organization, focal adhesion formation, and cell force.","method":"Overexpression and knockdown in SH-SY5Y cells, Elastic Resonator Interference Stress Microscopy (ERISM), Western blot for ERK1/2 phosphorylation and NeuroD1, immunofluorescence for actin/focal adhesions","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biophysical and biochemical orthogonal methods, gain- and loss-of-function, single lab","pmids":["33088261"],"is_preprint":false},{"year":2020,"finding":"FRMD6 functions as a tumor suppressor in prostate cancer. CRISPR/Cas9 knockout of FRMD6 leads to enrichment of Hippo/YAP and c-MYC signaling (phospho-proteomic profiling). Frmd6/Pten double knockout in mouse prostate causes high-grade prostatic intraepithelial neoplasia and hyperproliferation, more severe than Pten single knockout alone, establishing FRMD6 as a cooperating suppressor with PTEN.","method":"CRISPR/Cas9 knockout, overexpression in PC cell lines, transcriptomic/proteomic/phospho-proteomic profiling, orthotopic mouse knockout model with histopathology","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double-KO mouse model), multi-omic profiling, multiple orthogonal methods across cell lines and mouse model","pmids":["33249427"],"is_preprint":false},{"year":2022,"finding":"Willin/FRMD6 knockdown leads to mitochondrial dysfunction, mitochondrial fragmentation, and upregulation of ERK1/2 signaling in hippocampal HT-22 cells and primary neurons. Amyloid-beta (Aβ) induces downregulation of Willin/FRMD6 protein expression. Increasing Willin/FRMD6 expression rescues Aβ-induced abnormalities in mitochondrial morphology, function, and energetics.","method":"siRNA knockdown, overexpression, Aβ treatment, mitochondrial morphology imaging, mitochondrial function assays (energetics), Western blot for ERK1/2 in HT-22 and primary mouse neurons","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple mitochondrial readouts, rescue experiment, single lab","pmids":["36231104"],"is_preprint":false},{"year":2023,"finding":"FRMD6 interacts and co-localizes with mTOR and S6K in lung cancer cells, markedly enhances the interaction between mTOR and S6K, and increases phosphorylation of S6K and downstream S6. Knockout of FRMD6 in MEFs and mice inhibits mTOR signaling pathway activation, promoting lung cancer progression through mTOR pathway activation.","method":"Co-immunoprecipitation, co-localization (immunofluorescence), overexpression and knockout (FRMD6 KO MEFs and mice), Western blot for pS6K and pS6","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, co-localization, in vivo KO validation, single lab, multiple orthogonal methods","pmids":["37060526"],"is_preprint":false},{"year":2024,"finding":"FRMD6 is upregulated in senescent fibroblasts, directly interacts with and activates MST kinase, leading to YAP/TAZ inactivation (increased inhibitory phosphorylation). FRMD6 overexpression alone is sufficient to induce senescence; FRMD6 silencing mitigates senescence. FRMD6 expression in senescent cells is regulated by p53 and SMAD transcription factors and induced by TGF-β.","method":"Proteomic analysis in senescent IMR90, FRMD6 overexpression and silencing, Co-IP for FRMD6-MST kinase interaction, Western blot for pYAP/pTAZ, TGF-β treatment, immunofluorescence in patient fibroblastic foci","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction (Co-IP), gain- and loss-of-function, in vivo tissue validation, proteomics, multiple orthogonal methods in single rigorous study","pmids":["38926528"],"is_preprint":false},{"year":2026,"finding":"FRMD6 was identified as the most significantly altered upstream regulator in Si3N4 nanoparticle-treated endothelial cells. FRMD6 knockdown restores adherens junction stability and abolishes Si3N4-mediated pro-angiogenic effects, including VE-cadherin phosphorylation and AJ dissociation. Local FRMD6 knockdown in vivo impairs Si3N4-promoted neovascularization and bone regeneration.","method":"Transcriptome sequencing, FRMD6 knockdown, Western blot for pVE-cadherin, angiogenesis assays, rat calvarial defect in vivo model","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with specific molecular readout (pVE-cadherin), in vivo validation, single lab, multiple assays","pmids":["41916139"],"is_preprint":false},{"year":2026,"finding":"L-Theanine (via TAS1R1 receptor) promotes FRMD6 expression, which enhances the interaction between FRMD6 and mTOR, promotes mTOR translocation from cytoplasm to the lysosomal surface, and activates mTORC1 signaling to promote milk synthesis in bovine mammary epithelial cells.","method":"TAS1R1 and FRMD6 knockdown and overexpression, transcriptome sequencing, Co-immunoprecipitation for FRMD6-mTOR interaction, subcellular fractionation/immunofluorescence for mTOR localization, Western blot for mTORC1 targets","journal":"The Journal of nutritional biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interaction, mTOR localization assay with functional consequence, multiple loss/gain-of-function experiments, single lab","pmids":["42097464"],"is_preprint":false}],"current_model":"FRMD6/Willin is a FERM domain-containing protein that acts as an upstream activator of the Hippo signaling pathway by directly interacting with and activating MST kinase, leading to LATS1/2-mediated phosphorylation and cytoplasmic sequestration of YAP/TAZ; it localizes to apical junctional complexes via nectin binding, where it recruits aPKC to suppress ROCK junctional localization and regulate epithelial apical morphology; it also modulates RTK (c-Met, PDGFR) and mTOR/S6K signaling, regulates ERK1/2-dependent neuronal differentiation and mitochondrial integrity, and influences cell migration and senescence through the Hippo-YAP-CCN3 axis downstream of p53/SMAD/TGF-β."},"narrative":{"mechanistic_narrative":"FRMD6 (Willin) is a FERM domain-containing membrane-associated protein that functions as an upstream activator of Hippo signaling and a regulator of epithelial architecture, growth-factor signaling, and cellular senescence [PMID:21666719, PMID:38926528]. Through its N-terminal FERM domain it binds phospholipids and co-localizes with cortical actin at the plasma membrane, and this membrane association is induced by EGF stimulation [PMID:16137681]. FRMD6 activates the Hippo cascade by directly interacting with and activating MST kinase, increasing phosphorylation of MST1/2, LATS1, and YAP and driving YAP/TAZ cytoplasmic sequestration and inactivation; this activity is antagonized by ezrin and depends on the FERM domain [PMID:21666719, PMID:38926528]. At apical junctional complexes, FRMD6 is recruited via nectin binding (downstream of the nectin–afadin interaction) and, together with Par3, recruits aPKC/Par6 to control epithelial apical morphology by suppressing junctional ROCK localization [PMID:21685893, PMID:22512338]. Beyond Hippo, FRMD6 restrains receptor tyrosine kinase signaling — inhibiting c-Met, PDGFR, and downstream ERK/AKT — and modulates mTOR/S6K signaling by promoting mTOR–S6K interaction and mTOR translocation to the lysosomal surface [PMID:27661120, PMID:37060526, PMID:42097464]. FRMD6 acts as a tumor suppressor cooperating with PTEN in prostate cancer and is induced during senescence under p53/SMAD/TGF-β control, where its overexpression is sufficient to drive senescence [PMID:33249427, PMID:38926528]. It also regulates ERK1/2-dependent neuronal differentiation, mitochondrial integrity, and endothelial adherens-junction stability [PMID:33088261, PMID:36231104, PMID:41916139].","teleology":[{"year":2005,"claim":"Established the basic biochemical identity of FRMD6 as a FERM domain protein with membrane-targeting capacity, framing it as a cortical adaptor responsive to growth-factor signaling.","evidence":"Immunofluorescence co-localization, cytochalasin D treatment, EGF stimulation, and phospholipid binding assays","pmids":["16137681"],"confidence":"Medium","gaps":["No downstream signaling partners identified at this stage","Mechanism of EGF-induced membrane recruitment not resolved"]},{"year":2011,"claim":"Connected FRMD6 to a defined signaling output by showing it activates the Hippo kinase cascade through its FERM domain and antagonizes YAP, defining it as an upstream Hippo regulator.","evidence":"Ectopic expression and FERM truncation constructs with phospho-Western readouts and knockdown phenotyping in MCF10A cells","pmids":["21666719"],"confidence":"Medium","gaps":["Direct kinase target not biochemically demonstrated in this study","Mechanism of ezrin antagonism unresolved"]},{"year":2011,"claim":"Resolved how FRMD6 controls epithelial apical morphology by placing it in a Willin/Par3–aPKC–ROCK pathway that suppresses junctional ROCK.","evidence":"Single and double siRNA depletion with epistasis analysis, immunofluorescence, and Western blot in epithelial cells","pmids":["21685893"],"confidence":"High","gaps":["Direct binding interface with aPKC/Par6 not mapped","Relationship to FRMD6's Hippo activity not integrated"]},{"year":2012,"claim":"Identified the molecular basis of FRMD6 junctional recruitment, showing nectin binding (downstream of nectin–afadin) localizes FRMD6 to the apical junctional complex.","evidence":"Co-immunoprecipitation, immunofluorescence, and knockdown of nectins/afadin with FRMD6 localization readout","pmids":["22512338"],"confidence":"Medium","gaps":["Binding domain on FRMD6 for nectin not mapped","Single-lab Co-IP without reciprocal structural validation"]},{"year":2013,"claim":"Demonstrated cell-type-specific functional consequences of FRMD6-driven Hippo activation, linking YAP cytoplasmic translocation to suppressed proliferation but enhanced directional migration in nerve fibroblasts.","evidence":"Expression analysis, pYAP-Ser127 Western blot, YAP localization imaging, and proliferation/migration assays","pmids":["23593160"],"confidence":"Medium","gaps":["Mechanism coupling Hippo activation to migration not defined","No upstream activating signal identified"]},{"year":2016,"claim":"Revealed a Hippo-independent tumor-suppressive arm in which FRMD6 restrains receptor tyrosine kinase (c-Met, PDGFR) and downstream ERK/AKT signaling in glioblastoma.","evidence":"Overexpression/knockdown in GBM lines, RTK/ERK/AKT phospho-Westerns, and xenograft rescue with constitutively active TPR-Met","pmids":["27661120"],"confidence":"Medium","gaps":["Molecular mechanism of RTK inhibition unknown","Why Hippo activation is absent in GBM not explained"]},{"year":2019,"claim":"Positioned FRMD6 as a receptor-recruited Hippo effector, acting downstream of BDNF-TrkB-T1 to promote endothelial migration in aged cells.","evidence":"Co-IP/interaction, knockdown, and migration assay with pathway epistasis in aged cardiac microvascular endothelial cells","pmids":["30667167"],"confidence":"Medium","gaps":["Direct TrkB-T1–FRMD6 binding interface not defined","Single-lab epistasis without reciprocal validation"]},{"year":2020,"claim":"Extended FRMD6's reach to neuronal mechanobiology, showing it inversely controls ERK1/2 and NeuroD1 to shape neuronal differentiation, cytoskeletal organization, and cellular force.","evidence":"Gain/loss-of-function in SH-SY5Y cells with ERISM force microscopy, phospho-ERK1/2 and NeuroD1 Westerns, and actin/focal-adhesion imaging","pmids":["33088261"],"confidence":"Medium","gaps":["Mechanism linking FRMD6 to ERK1/2 suppression unresolved","Relationship to Hippo signaling in neurons unclear"]},{"year":2020,"claim":"Provided in vivo genetic evidence for FRMD6 as a tumor suppressor cooperating with PTEN, with knockout enriching Hippo/YAP and c-MYC signaling in prostate.","evidence":"CRISPR/Cas9 knockout, multi-omic profiling, and Frmd6/Pten double-knockout mouse model with histopathology","pmids":["33249427"],"confidence":"High","gaps":["Direct molecular link between FRMD6 loss and c-MYC enrichment not defined","Whether PTEN cooperation is Hippo-dependent unresolved"]},{"year":2022,"claim":"Connected FRMD6 to mitochondrial integrity and Alzheimer-relevant stress, showing its loss causes mitochondrial fragmentation and ERK1/2 upregulation and that Aβ downregulates FRMD6.","evidence":"siRNA knockdown, overexpression, Aβ treatment, and mitochondrial morphology/function assays in HT-22 and primary neurons with rescue","pmids":["36231104"],"confidence":"Medium","gaps":["Direct mechanism linking FRMD6 to mitochondrial dynamics unknown","How Aβ downregulates FRMD6 not defined"]},{"year":2023,"claim":"Defined a positive role for FRMD6 in mTOR signaling, showing it scaffolds mTOR–S6K interaction to drive S6K/S6 phosphorylation, with knockout promoting lung cancer.","evidence":"Reciprocal Co-IP, co-localization, overexpression, and FRMD6-KO MEFs/mice with pS6K/pS6 Westerns","pmids":["37060526"],"confidence":"Medium","gaps":["Apparent context-dependent opposite roles of FRMD6 (suppressor vs mTOR activator) not reconciled","Structural basis of mTOR–S6K scaffolding unknown"]},{"year":2024,"claim":"Established a direct biochemical mechanism and transcriptional control, showing FRMD6 directly binds and activates MST kinase to inactivate YAP/TAZ and is sufficient to drive senescence under p53/SMAD/TGF-β regulation.","evidence":"Senescent IMR90 proteomics, gain/loss-of-function, FRMD6–MST Co-IP, pYAP/pTAZ Westerns, TGF-β treatment, and patient fibroblastic foci imaging","pmids":["38926528"],"confidence":"High","gaps":["FRMD6–MST binding interface not structurally resolved","How senescence-inducing FRMD6 relates to its growth-factor functions unclear"]},{"year":2026,"claim":"Implicated FRMD6 in endothelial adherens-junction control and angiogenesis, showing its knockdown stabilizes junctions and blocks nanoparticle-driven VE-cadherin phosphorylation and neovascularization.","evidence":"Transcriptome sequencing, FRMD6 knockdown, pVE-cadherin Western, angiogenesis assays, and rat calvarial defect in vivo model","pmids":["41916139"],"confidence":"Medium","gaps":["Direct molecular link between FRMD6 and VE-cadherin phosphorylation undefined","Pathway connecting Si3N4 sensing to FRMD6 unknown"]},{"year":2026,"claim":"Extended FRMD6's mTOR-activating role to nutrient signaling, showing TAS1R1-induced FRMD6 promotes mTOR lysosomal translocation and mTORC1 activation to drive milk synthesis.","evidence":"TAS1R1/FRMD6 knockdown and overexpression, transcriptome sequencing, FRMD6–mTOR Co-IP, mTOR localization fractionation/imaging, and mTORC1-target Westerns in bovine mammary cells","pmids":["42097464"],"confidence":"Medium","gaps":["Mechanism by which FRMD6 promotes mTOR lysosomal recruitment unresolved","Single-lab Co-IP without reciprocal structural validation"]},{"year":null,"claim":"How FRMD6 switches between opposing outputs — Hippo-mediated tumor suppression versus mTOR/growth-promoting scaffolding — across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the FERM domain bound to MST or mTOR","Determinants selecting Hippo versus RTK/mTOR engagement in different tissues unknown","Direct substrate-level mechanism for ERK1/2 and RTK suppression undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,11,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,6,11]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,8,10]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,3,12]}],"complexes":["apical junctional complex"],"partners":["MST1","NECTIN","APKC","PAR6","MTOR","S6K","TRKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96NE9","full_name":"FERM domain-containing protein 6","aliases":["Willin"],"length_aa":622,"mass_kda":72.0,"function":"","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96NE9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRMD6","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FRMD6","total_profiled":1310},"omim":[{"mim_id":"614555","title":"FERM DOMAIN-CONTAINING PROTEIN 6; FRMD6","url":"https://www.omim.org/entry/614555"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FRMD6"},"hgnc":{"alias_symbol":["MGC17921","willin","EX1"],"prev_symbol":["C14orf31"]},"alphafold":{"accession":"Q96NE9","domains":[{"cath_id":"3.10.20.90","chopping":"12-91_99-114","consensus_level":"high","plddt":85.3299,"start":12,"end":114},{"cath_id":"1.20.80.10","chopping":"120-223","consensus_level":"high","plddt":95.7873,"start":120,"end":223},{"cath_id":"2.30.29.30","chopping":"230-350_453-464_474-503","consensus_level":"medium","plddt":78.5591,"start":230,"end":503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NE9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NE9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NE9-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRMD6","jax_strain_url":"https://www.jax.org/strain/search?query=FRMD6"},"sequence":{"accession":"Q96NE9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NE9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NE9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NE9"}},"corpus_meta":[{"pmid":"2417625","id":"PMC_2417625","title":"Amide 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N-terminus, is capable of binding phospholipids, and can co-localize with actin at the plasma membrane. Plasma membrane localization is not influenced by cytochalasin D-induced actin disruption but is induced by the addition of epidermal growth factor.\",\n      \"method\": \"Immunofluorescence/co-localization, cytochalasin D treatment, EGF stimulation, phospholipid binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with pharmacological manipulation and functional stimulus, single lab, multiple assays\",\n      \"pmids\": [\"16137681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Willin/FRMD6 activates the Hippo signaling pathway in mammalian cells: ectopic willin expression increases phosphorylation of MST1/2, LATS1, and YAP. This effect can be antagonized by ezrin. In MCF10A cells, willin overexpression antagonizes YAP activity via its N-terminal FERM domain. Loss of willin displays epithelial-to-mesenchymal transition features.\",\n      \"method\": \"Ectopic expression, Western blot for phosphorylated pathway components, FERM domain truncation constructs, knockdown with phenotypic readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal domain mapping and phosphorylation assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21666719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Willin/FRMD6 recruits aPKC and Par6 to the apical junctional complex (AJC) independently of Par3. Simultaneous depletion of Willin and Par3 removes aPKC/Par6 from AJCs and induces apical constriction via upregulation of AJC-associated ROCK levels. aPKC phosphorylates ROCK and suppresses its junctional localization, defining a Willin/Par3-aPKC-ROCK pathway controlling epithelial apical morphology.\",\n      \"method\": \"siRNA depletion (single and double knockdown), immunofluorescence, Western blot, genetic epistasis analysis in epithelial cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by double-KD rescue, reciprocal localization experiments, pathway ordering by multiple orthogonal methods, published in high-tier journal\",\n      \"pmids\": [\"21685893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Willin/FRMD6 binds to nectins (Ig-family adhesion proteins) at the apical junctional complex, and this binding is required for junctional recruitment of Willin. Nectin positioning at the AJC depends on afadin binding, placing the nectin-afadin interaction upstream of Willin localization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, knockdown of nectins and afadin with Willin localization readout\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP binding and localization experiments with functional consequence, single lab, two methods\",\n      \"pmids\": [\"22512338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In mammalian sciatic nerve fibroblasts, Willin/FRMD6 is predominantly expressed and its expression activates the Hippo signaling cascade, inducing YAP translocation from nucleus to cytoplasm (Ser127 phosphorylation). Willin expression inhibits cellular proliferation but induces faster directional migration and increased expression of nerve regeneration factors.\",\n      \"method\": \"Expression analysis, Western blot for pYAP-Ser127, immunofluorescence for YAP localization, proliferation and migration assays (scratch assay)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — YAP subcellular localization with functional consequence, proliferation and migration phenotype, single lab, multiple assays\",\n      \"pmids\": [\"23593160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FRMD6 inhibits activation of receptor tyrosine kinases c-Met and PDGFR and their downstream ERK and AKT kinases in glioblastoma cells. Increased FRMD6 expression displays little effect on the Hippo pathway in GBM cells (negative result for Hippo activation). Expression of constitutively active c-Met (TPR-Met) largely reverses the anti-GBM effect of FRMD6 in vivo, placing FRMD6 upstream of RTK activity.\",\n      \"method\": \"Overexpression and knockdown in GBM cell lines, Western blot for RTK/ERK/AKT phosphorylation, xenograft rescue with TPR-Met constitutively active construct\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo epistasis rescue experiment plus in vitro phosphorylation assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27661120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In aged cardiac microvascular endothelial cells, BDNF-TrkB-T1 signaling recruits Willin/FRMD6 as a downstream effector to activate the Hippo pathway, which promotes cell migration. Willin acts downstream of TrkB-T1 in the BDNF-TrkB-T1-Willin-Hippo pathway.\",\n      \"method\": \"Co-immunoprecipitation/protein interaction, knockdown, cell migration assay, pathway epistasis in aged CMECs\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway epistasis established by knockdown with migration readout, receptor-effector interaction, single lab\",\n      \"pmids\": [\"30667167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Willin/FRMD6 expression influences the mechanical phenotype and neuronal differentiation of SH-SY5Y neuronal cells by inversely regulating ERK1/2 pathway activity and downstream transcription factor NeuroD1. Changes in Willin/FRMD6 levels alter cell morphology, neurite-like extension formation, actin stress fiber organization, focal adhesion formation, and cell force.\",\n      \"method\": \"Overexpression and knockdown in SH-SY5Y cells, Elastic Resonator Interference Stress Microscopy (ERISM), Western blot for ERK1/2 phosphorylation and NeuroD1, immunofluorescence for actin/focal adhesions\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biophysical and biochemical orthogonal methods, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"33088261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FRMD6 functions as a tumor suppressor in prostate cancer. CRISPR/Cas9 knockout of FRMD6 leads to enrichment of Hippo/YAP and c-MYC signaling (phospho-proteomic profiling). Frmd6/Pten double knockout in mouse prostate causes high-grade prostatic intraepithelial neoplasia and hyperproliferation, more severe than Pten single knockout alone, establishing FRMD6 as a cooperating suppressor with PTEN.\",\n      \"method\": \"CRISPR/Cas9 knockout, overexpression in PC cell lines, transcriptomic/proteomic/phospho-proteomic profiling, orthotopic mouse knockout model with histopathology\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double-KO mouse model), multi-omic profiling, multiple orthogonal methods across cell lines and mouse model\",\n      \"pmids\": [\"33249427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Willin/FRMD6 knockdown leads to mitochondrial dysfunction, mitochondrial fragmentation, and upregulation of ERK1/2 signaling in hippocampal HT-22 cells and primary neurons. Amyloid-beta (Aβ) induces downregulation of Willin/FRMD6 protein expression. Increasing Willin/FRMD6 expression rescues Aβ-induced abnormalities in mitochondrial morphology, function, and energetics.\",\n      \"method\": \"siRNA knockdown, overexpression, Aβ treatment, mitochondrial morphology imaging, mitochondrial function assays (energetics), Western blot for ERK1/2 in HT-22 and primary mouse neurons\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple mitochondrial readouts, rescue experiment, single lab\",\n      \"pmids\": [\"36231104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FRMD6 interacts and co-localizes with mTOR and S6K in lung cancer cells, markedly enhances the interaction between mTOR and S6K, and increases phosphorylation of S6K and downstream S6. Knockout of FRMD6 in MEFs and mice inhibits mTOR signaling pathway activation, promoting lung cancer progression through mTOR pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization (immunofluorescence), overexpression and knockout (FRMD6 KO MEFs and mice), Western blot for pS6K and pS6\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, co-localization, in vivo KO validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37060526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FRMD6 is upregulated in senescent fibroblasts, directly interacts with and activates MST kinase, leading to YAP/TAZ inactivation (increased inhibitory phosphorylation). FRMD6 overexpression alone is sufficient to induce senescence; FRMD6 silencing mitigates senescence. FRMD6 expression in senescent cells is regulated by p53 and SMAD transcription factors and induced by TGF-β.\",\n      \"method\": \"Proteomic analysis in senescent IMR90, FRMD6 overexpression and silencing, Co-IP for FRMD6-MST kinase interaction, Western blot for pYAP/pTAZ, TGF-β treatment, immunofluorescence in patient fibroblastic foci\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction (Co-IP), gain- and loss-of-function, in vivo tissue validation, proteomics, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38926528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FRMD6 was identified as the most significantly altered upstream regulator in Si3N4 nanoparticle-treated endothelial cells. FRMD6 knockdown restores adherens junction stability and abolishes Si3N4-mediated pro-angiogenic effects, including VE-cadherin phosphorylation and AJ dissociation. Local FRMD6 knockdown in vivo impairs Si3N4-promoted neovascularization and bone regeneration.\",\n      \"method\": \"Transcriptome sequencing, FRMD6 knockdown, Western blot for pVE-cadherin, angiogenesis assays, rat calvarial defect in vivo model\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with specific molecular readout (pVE-cadherin), in vivo validation, single lab, multiple assays\",\n      \"pmids\": [\"41916139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"L-Theanine (via TAS1R1 receptor) promotes FRMD6 expression, which enhances the interaction between FRMD6 and mTOR, promotes mTOR translocation from cytoplasm to the lysosomal surface, and activates mTORC1 signaling to promote milk synthesis in bovine mammary epithelial cells.\",\n      \"method\": \"TAS1R1 and FRMD6 knockdown and overexpression, transcriptome sequencing, Co-immunoprecipitation for FRMD6-mTOR interaction, subcellular fractionation/immunofluorescence for mTOR localization, Western blot for mTORC1 targets\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interaction, mTOR localization assay with functional consequence, multiple loss/gain-of-function experiments, single lab\",\n      \"pmids\": [\"42097464\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRMD6/Willin is a FERM domain-containing protein that acts as an upstream activator of the Hippo signaling pathway by directly interacting with and activating MST kinase, leading to LATS1/2-mediated phosphorylation and cytoplasmic sequestration of YAP/TAZ; it localizes to apical junctional complexes via nectin binding, where it recruits aPKC to suppress ROCK junctional localization and regulate epithelial apical morphology; it also modulates RTK (c-Met, PDGFR) and mTOR/S6K signaling, regulates ERK1/2-dependent neuronal differentiation and mitochondrial integrity, and influences cell migration and senescence through the Hippo-YAP-CCN3 axis downstream of p53/SMAD/TGF-β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRMD6 (Willin) is a FERM domain-containing membrane-associated protein that functions as an upstream activator of Hippo signaling and a regulator of epithelial architecture, growth-factor signaling, and cellular senescence [#1, #11]. Through its N-terminal FERM domain it binds phospholipids and co-localizes with cortical actin at the plasma membrane, and this membrane association is induced by EGF stimulation [#0]. FRMD6 activates the Hippo cascade by directly interacting with and activating MST kinase, increasing phosphorylation of MST1/2, LATS1, and YAP and driving YAP/TAZ cytoplasmic sequestration and inactivation; this activity is antagonized by ezrin and depends on the FERM domain [#1, #11]. At apical junctional complexes, FRMD6 is recruited via nectin binding (downstream of the nectin–afadin interaction) and, together with Par3, recruits aPKC/Par6 to control epithelial apical morphology by suppressing junctional ROCK localization [#2, #3]. Beyond Hippo, FRMD6 restrains receptor tyrosine kinase signaling — inhibiting c-Met, PDGFR, and downstream ERK/AKT — and modulates mTOR/S6K signaling by promoting mTOR–S6K interaction and mTOR translocation to the lysosomal surface [#5, #10, #13]. FRMD6 acts as a tumor suppressor cooperating with PTEN in prostate cancer and is induced during senescence under p53/SMAD/TGF-β control, where its overexpression is sufficient to drive senescence [#8, #11]. It also regulates ERK1/2-dependent neuronal differentiation, mitochondrial integrity, and endothelial adherens-junction stability [#7, #9, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the basic biochemical identity of FRMD6 as a FERM domain protein with membrane-targeting capacity, framing it as a cortical adaptor responsive to growth-factor signaling.\",\n      \"evidence\": \"Immunofluorescence co-localization, cytochalasin D treatment, EGF stimulation, and phospholipid binding assays\",\n      \"pmids\": [\"16137681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No downstream signaling partners identified at this stage\", \"Mechanism of EGF-induced membrane recruitment not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected FRMD6 to a defined signaling output by showing it activates the Hippo kinase cascade through its FERM domain and antagonizes YAP, defining it as an upstream Hippo regulator.\",\n      \"evidence\": \"Ectopic expression and FERM truncation constructs with phospho-Western readouts and knockdown phenotyping in MCF10A cells\",\n      \"pmids\": [\"21666719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase target not biochemically demonstrated in this study\", \"Mechanism of ezrin antagonism unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how FRMD6 controls epithelial apical morphology by placing it in a Willin/Par3–aPKC–ROCK pathway that suppresses junctional ROCK.\",\n      \"evidence\": \"Single and double siRNA depletion with epistasis analysis, immunofluorescence, and Western blot in epithelial cells\",\n      \"pmids\": [\"21685893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with aPKC/Par6 not mapped\", \"Relationship to FRMD6's Hippo activity not integrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the molecular basis of FRMD6 junctional recruitment, showing nectin binding (downstream of nectin–afadin) localizes FRMD6 to the apical junctional complex.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence, and knockdown of nectins/afadin with FRMD6 localization readout\",\n      \"pmids\": [\"22512338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding domain on FRMD6 for nectin not mapped\", \"Single-lab Co-IP without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated cell-type-specific functional consequences of FRMD6-driven Hippo activation, linking YAP cytoplasmic translocation to suppressed proliferation but enhanced directional migration in nerve fibroblasts.\",\n      \"evidence\": \"Expression analysis, pYAP-Ser127 Western blot, YAP localization imaging, and proliferation/migration assays\",\n      \"pmids\": [\"23593160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling Hippo activation to migration not defined\", \"No upstream activating signal identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a Hippo-independent tumor-suppressive arm in which FRMD6 restrains receptor tyrosine kinase (c-Met, PDGFR) and downstream ERK/AKT signaling in glioblastoma.\",\n      \"evidence\": \"Overexpression/knockdown in GBM lines, RTK/ERK/AKT phospho-Westerns, and xenograft rescue with constitutively active TPR-Met\",\n      \"pmids\": [\"27661120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of RTK inhibition unknown\", \"Why Hippo activation is absent in GBM not explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Positioned FRMD6 as a receptor-recruited Hippo effector, acting downstream of BDNF-TrkB-T1 to promote endothelial migration in aged cells.\",\n      \"evidence\": \"Co-IP/interaction, knockdown, and migration assay with pathway epistasis in aged cardiac microvascular endothelial cells\",\n      \"pmids\": [\"30667167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TrkB-T1–FRMD6 binding interface not defined\", \"Single-lab epistasis without reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended FRMD6's reach to neuronal mechanobiology, showing it inversely controls ERK1/2 and NeuroD1 to shape neuronal differentiation, cytoskeletal organization, and cellular force.\",\n      \"evidence\": \"Gain/loss-of-function in SH-SY5Y cells with ERISM force microscopy, phospho-ERK1/2 and NeuroD1 Westerns, and actin/focal-adhesion imaging\",\n      \"pmids\": [\"33088261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking FRMD6 to ERK1/2 suppression unresolved\", \"Relationship to Hippo signaling in neurons unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided in vivo genetic evidence for FRMD6 as a tumor suppressor cooperating with PTEN, with knockout enriching Hippo/YAP and c-MYC signaling in prostate.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, multi-omic profiling, and Frmd6/Pten double-knockout mouse model with histopathology\",\n      \"pmids\": [\"33249427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between FRMD6 loss and c-MYC enrichment not defined\", \"Whether PTEN cooperation is Hippo-dependent unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected FRMD6 to mitochondrial integrity and Alzheimer-relevant stress, showing its loss causes mitochondrial fragmentation and ERK1/2 upregulation and that Aβ downregulates FRMD6.\",\n      \"evidence\": \"siRNA knockdown, overexpression, Aβ treatment, and mitochondrial morphology/function assays in HT-22 and primary neurons with rescue\",\n      \"pmids\": [\"36231104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking FRMD6 to mitochondrial dynamics unknown\", \"How Aβ downregulates FRMD6 not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a positive role for FRMD6 in mTOR signaling, showing it scaffolds mTOR–S6K interaction to drive S6K/S6 phosphorylation, with knockout promoting lung cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, co-localization, overexpression, and FRMD6-KO MEFs/mice with pS6K/pS6 Westerns\",\n      \"pmids\": [\"37060526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent context-dependent opposite roles of FRMD6 (suppressor vs mTOR activator) not reconciled\", \"Structural basis of mTOR–S6K scaffolding unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a direct biochemical mechanism and transcriptional control, showing FRMD6 directly binds and activates MST kinase to inactivate YAP/TAZ and is sufficient to drive senescence under p53/SMAD/TGF-β regulation.\",\n      \"evidence\": \"Senescent IMR90 proteomics, gain/loss-of-function, FRMD6–MST Co-IP, pYAP/pTAZ Westerns, TGF-β treatment, and patient fibroblastic foci imaging\",\n      \"pmids\": [\"38926528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FRMD6–MST binding interface not structurally resolved\", \"How senescence-inducing FRMD6 relates to its growth-factor functions unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated FRMD6 in endothelial adherens-junction control and angiogenesis, showing its knockdown stabilizes junctions and blocks nanoparticle-driven VE-cadherin phosphorylation and neovascularization.\",\n      \"evidence\": \"Transcriptome sequencing, FRMD6 knockdown, pVE-cadherin Western, angiogenesis assays, and rat calvarial defect in vivo model\",\n      \"pmids\": [\"41916139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FRMD6 and VE-cadherin phosphorylation undefined\", \"Pathway connecting Si3N4 sensing to FRMD6 unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended FRMD6's mTOR-activating role to nutrient signaling, showing TAS1R1-induced FRMD6 promotes mTOR lysosomal translocation and mTORC1 activation to drive milk synthesis.\",\n      \"evidence\": \"TAS1R1/FRMD6 knockdown and overexpression, transcriptome sequencing, FRMD6–mTOR Co-IP, mTOR localization fractionation/imaging, and mTORC1-target Westerns in bovine mammary cells\",\n      \"pmids\": [\"42097464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FRMD6 promotes mTOR lysosomal recruitment unresolved\", \"Single-lab Co-IP without reciprocal structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FRMD6 switches between opposing outputs — Hippo-mediated tumor suppression versus mTOR/growth-promoting scaffolding — across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the FERM domain bound to MST or mTOR\", \"Determinants selecting Hippo versus RTK/mTOR engagement in different tissues unknown\", \"Direct substrate-level mechanism for ERK1/2 and RTK suppression undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 11, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8, 10]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 3, 12]}\n    ],\n    \"complexes\": [\"apical junctional complex\"],\n    \"partners\": [\"MST1\", \"nectin\", \"aPKC\", \"Par6\", \"mTOR\", \"S6K\", \"TrkB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}