{"gene":"FRMD6","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2005,"finding":"FRMD6/Willin contains a FERM domain at its N-terminus, is capable of binding phospholipids, and localizes either in the cytoplasm or at the plasma membrane where it co-localizes with actin; plasma membrane localization is not affected by cytochalasin D-induced actin disruption but is induced by EGF treatment.","method":"Subcellular fractionation, co-localization imaging, cytochalasin D treatment, EGF stimulation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple imaging/biochemical methods but no functional rescue or mutagenesis","pmids":["16137681"],"is_preprint":false},{"year":2011,"finding":"Willin/FRMD6 expression activates the Hippo signaling pathway kinases MST1/2 and LATS1 and increases YAP phosphorylation in mammalian cells; this effect can be antagonized by ezrin. The N-terminal FERM domain of Willin is required to antagonize YAP activity. Loss of Willin in MCF10A cells induces epithelial-to-mesenchymal transition features.","method":"Ectopic expression in D. melanogaster and mammalian cells, phospho-Western blotting for MST1/2, LATS1, YAP; FERM domain deletion constructs; shRNA knockdown with EMT readout","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (phospho-WB, domain deletion, KD phenotype) in single study with clear mechanistic pathway placement","pmids":["21666719"],"is_preprint":false},{"year":2011,"finding":"Willin/FRMD6 recruits aPKC and Par6 to apical junctional complexes (AJCs) independently of Par3. Simultaneous depletion of Willin and Par3 removes aPKC/Par6 from AJCs and induces apical constriction via upregulated ROCK at junctions. aPKC phosphorylates ROCK and suppresses its junctional localization, establishing a Willin/Par3–aPKC–ROCK pathway controlling epithelial apical morphology.","method":"siRNA knockdown (single and double), immunofluorescence localization, ROCK inhibitor rescue, co-immunoprecipitation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via double knockdown, rescue experiments, and direct localization with functional consequence","pmids":["21685893"],"is_preprint":false},{"year":2012,"finding":"Willin/FRMD6 binds directly to nectins (Ig-family cell adhesion proteins) at apical junctional complexes; this nectin interaction mediates the junctional recruitment of Willin. Nectin positioning at AJCs depends on afadin binding to nectins.","method":"Co-immunoprecipitation, knockdown of afadin with loss-of-Willin junctional localization as readout, immunofluorescence","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus localization data from single lab","pmids":["22512338"],"is_preprint":false},{"year":2013,"finding":"In mammalian sciatic nerve fibroblasts, Willin/FRMD6 expression activates the Hippo signaling cascade and induces YAP translocation from the nucleus to the cytoplasm (Ser127 phosphorylation), inhibits cellular proliferation, and promotes directional migration toward scratch closure.","method":"Overexpression, Western blotting for YAP phosphorylation, nuclear/cytoplasmic fractionation, scratch wound migration assay, proliferation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, single lab","pmids":["23593160"],"is_preprint":false},{"year":2016,"finding":"FRMD6 inhibits glioblastoma cell proliferation/invasion by suppressing activation of receptor tyrosine kinases c-Met and PDGFR and their downstream ERK and AKT kinases, rather than through the core Hippo kinase cascade. Expression of constitutively active TPR-Met largely reverses the anti-GBM effect of FRMD6 in vivo, placing FRMD6 upstream of c-Met signaling.","method":"Overexpression and knockdown in GBM cells, xenograft in vivo models, phospho-Western blotting (c-Met, PDGFR, ERK, AKT), constitutively active c-Met rescue experiment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via constitutively active rescue plus phospho-proteomics, single lab","pmids":["27661120"],"is_preprint":false},{"year":2019,"finding":"In aged cardiac microvascular endothelial cells, BDNF signals through the truncated TrkB-T1 receptor to recruit Willin/FRMD6 as a downstream effector, which then activates the Hippo pathway to promote cell migration.","method":"Co-immunoprecipitation, siRNA knockdown, BDNF stimulation assay, migration assay","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus functional migration readout, single lab","pmids":["30667167"],"is_preprint":false},{"year":2020,"finding":"FRMD6 overexpression inhibits prostate cancer cell viability, proliferation, colony formation, and xenograft tumor growth, while CRISPR/Cas9 knockout promotes these phenotypes and leads to enrichment of Hippo/YAP and c-MYC signaling as shown by phospho-proteomics. In vivo, Frmd6/Pten double knockout in mouse prostate causes high-grade prostatic intraepithelial neoplasia and hyperproliferation beyond that seen with Pten loss alone.","method":"Overexpression and CRISPR/Cas9 KO, xenograft growth assay, transcriptomic/proteomic/phospho-proteomic profiling, orthotropic mouse double KO model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, OE, in vivo mouse model, proteomics) with clear mechanistic pathway placement","pmids":["33249427"],"is_preprint":false},{"year":2020,"finding":"Willin/FRMD6 expression in SH-SY5Y neuronal cells influences cell mechanical phenotype (cell force and actin stress fiber organization), neuronal differentiation, proliferation, and migration. Changes in Willin/FRMD6 expression inversely affect ERK1/2 signaling activity and downstream transcription factor NeuroD1, priming cells for retinoic acid-induced neuronal differentiation.","method":"Overexpression and siRNA knockdown, ERISM biophysical measurements, Western blotting for pERK1/2 and NeuroD1, neurite outgrowth and focal adhesion imaging, retinoic acid differentiation assay","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (biophysical + biochemical + cellular), single lab","pmids":["33088261"],"is_preprint":false},{"year":2022,"finding":"Willin/FRMD6 knockdown in mouse hippocampal HT-22 cells and primary mouse neurons leads to mitochondrial dysfunction and fragmentation, and upregulation of ERK1/2 signaling. Increased Willin/FRMD6 expression rescues Aβ-induced abnormalities in mitochondrial morphology, function, and energetics, positioning FRMD6 as a regulator of mitochondrial homeostasis in neurons.","method":"siRNA knockdown and overexpression, mitochondrial morphology imaging, mitochondrial function assays (oxygen consumption), Western blotting for pERK1/2, Aβ peptide treatment","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — loss and gain of function with rescue, multiple orthogonal readouts, single lab","pmids":["36231104"],"is_preprint":false},{"year":2023,"finding":"FRMD6 interacts with and activates MST kinase (co-immunoprecipitation demonstrated), leading to YAP/TAZ inactivation (increased inhibitory phosphorylation). FRMD6 overexpression alone induces senescence in cells and lung tissue, while FRMD6 silencing mitigates senescence. The downstream secretory factor CCN3 (regulated by YAP) can rescue FRMD6-induced senescence. FRMD6 expression is regulated upstream by p53 and SMAD transcription factors and is induced by TGF-β.","method":"Co-immunoprecipitation (FRMD6-MST interaction), overexpression and siRNA knockdown, phospho-Western blotting (YAP/TAZ), in vivo lung senescence model, proteomic analysis, TGF-β treatment, CCN3 rescue experiment","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 — Co-IP of FRMD6-MST interaction plus multiple orthogonal functional methods and in vivo model with clear mechanistic pathway","pmids":["38926528"],"is_preprint":false},{"year":2023,"finding":"FRMD6 interacts and colocalizes with mTOR and S6K, and markedly enhances the interaction between mTOR and S6K, increasing levels of phospho-S6K and downstream phospho-S6 in lung cancer cells. Knockout of FRMD6 inhibits mTOR pathway activation in MEFs and mice, establishing FRMD6 as an activator of mTOR signaling in lung cancer.","method":"Co-immunoprecipitation (FRMD6-mTOR, FRMD6-S6K), colocalization imaging, phospho-Western blotting (pS6K, pS6), FRMD6 knockout MEFs and mice","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo KO validation, single lab","pmids":["37060526"],"is_preprint":false},{"year":2026,"finding":"FRMD6 knockdown in endothelial cells restores adherens junction (AJ) stability and abolishes Si3N4 nanoparticle-mediated pro-angiogenic effects. FRMD6 was identified as the most significantly upregulated upstream regulator mediating Si3N4 NP-induced phosphorylation of VE-cadherin and AJ dissociation, establishing FRMD6 as an upstream regulator of VE-cadherin phosphorylation in angiogenesis.","method":"siRNA knockdown, transcriptome sequencing, Western blotting for VE-cadherin phosphorylation, in vivo rat calvarial defect model with local FRMD6 knockdown","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 — knockdown with functional rescue in vivo and in vitro with defined molecular target, single lab","pmids":["41916139"],"is_preprint":false}],"current_model":"FRMD6/Willin is a FERM-domain protein that functions as an upstream activator of the Hippo signaling pathway by directly binding and activating MST kinase to promote YAP/TAZ phosphorylation and cytoplasmic sequestration; it also recruits aPKC to apical junctional complexes to suppress ROCK-dependent actomyosin contractility, interacts with nectins for junctional localization, inhibits RTK (c-Met, PDGFR) and promotes ERK signaling in neuronal cells, activates the mTOR pathway by scaffolding mTOR-S6K interactions, regulates mitochondrial homeostasis, and acts downstream of TrkB-T1/BDNF signaling to promote cell migration."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing FRMD6 as a FERM-domain-containing, phospholipid-binding protein that localizes to the plasma membrane independently of actin, answering the basic question of its domain architecture and subcellular targeting.","evidence":"Subcellular fractionation, co-localization imaging, cytochalasin D and EGF stimulation in cultured cells","pmids":["16137681"],"confidence":"Medium","gaps":["No functional consequence of membrane localization was demonstrated","Phospholipid binding specificity not mapped to specific lipid species","Single lab characterization without independent replication"]},{"year":2011,"claim":"Two studies established FRMD6 as a dual regulator of epithelial cell biology: one showed it activates the Hippo kinase cascade (MST→LATS→pYAP) via its FERM domain, while the other demonstrated it recruits aPKC/Par6 to apical junctions to suppress ROCK-mediated apical constriction, answering how FRMD6 controls both proliferation and cell shape.","evidence":"Phospho-Western blotting of MST/LATS/YAP, FERM domain deletion, shRNA-induced EMT (Hippo); siRNA double knockdown, ROCK inhibitor rescue, co-IP (aPKC/Par6 pathway)","pmids":["21666719","21685893"],"confidence":"High","gaps":["Whether Hippo activation and aPKC recruitment are mechanistically linked or independent functions","No structural basis for FERM domain–MST interaction","Endogenous stoichiometry of FRMD6 at junctions not determined"]},{"year":2012,"claim":"Identifying nectins as direct binding partners that recruit FRMD6 to apical junctional complexes answered how FRMD6 is positioned at cell–cell contacts to exert its polarity and signaling functions.","evidence":"Co-immunoprecipitation of FRMD6–nectin, afadin knockdown abolishing junctional FRMD6 localization","pmids":["22512338"],"confidence":"Medium","gaps":["Binding interface between nectin and FRMD6 FERM domain not mapped","Single Co-IP study without reciprocal pull-down validation reported","Whether nectin binding is required for Hippo activation not tested"]},{"year":2013,"claim":"Demonstrating FRMD6-mediated YAP phosphorylation and nuclear exclusion in sciatic nerve fibroblasts extended Hippo activation beyond epithelial cells and linked it to migration and growth control in mesenchymal contexts.","evidence":"Overexpression with nuclear/cytoplasmic fractionation, scratch wound and proliferation assays in sciatic nerve fibroblasts","pmids":["23593160"],"confidence":"Medium","gaps":["Loss-of-function data in these cells not provided","Mechanism linking Hippo activation to directional migration not defined"]},{"year":2016,"claim":"Revealing that FRMD6 suppresses glioblastoma growth by inhibiting c-Met and PDGFR activation rather than through canonical Hippo kinases established a Hippo-independent tumor-suppressive mechanism and broadened FRMD6's signaling repertoire.","evidence":"Overexpression/knockdown in GBM cells, xenograft models, constitutively active TPR-Met rescue reversing FRMD6 anti-tumor effects","pmids":["27661120"],"confidence":"Medium","gaps":["Direct physical interaction between FRMD6 and RTKs not shown","How FRMD6 inhibits RTK activation mechanistically remains undefined","Single lab without independent replication in other GBM models"]},{"year":2019,"claim":"Placing FRMD6 downstream of BDNF/TrkB-T1 signaling in aged cardiac endothelial cells identified a receptor-level input that activates FRMD6 to promote Hippo-dependent migration, answering how FRMD6 is engaged by extracellular signals.","evidence":"Co-immunoprecipitation of TrkB-T1–FRMD6, siRNA knockdown, BDNF stimulation and migration assays in aged cardiac microvascular endothelial cells","pmids":["30667167"],"confidence":"Medium","gaps":["Direct versus adaptor-mediated interaction with TrkB-T1 not distinguished","Relevance to in vivo cardiac aging not validated genetically"]},{"year":2020,"claim":"Two studies expanded FRMD6's roles in cancer suppression and neuronal biology: CRISPR knockout in prostate cancer with in vivo double-KO mouse models confirmed tumor-suppressive function through Hippo/YAP and c-MYC, while neuronal studies showed FRMD6 modulates cell mechanics, ERK signaling, and NeuroD1-dependent differentiation.","evidence":"CRISPR KO, xenografts, Frmd6/Pten double-KO mouse prostate model, phospho-proteomics (prostate cancer); overexpression/knockdown with ERISM biophysics, pERK/NeuroD1 Western blots, retinoic acid differentiation (neuronal cells)","pmids":["33249427","33088261"],"confidence":"High","gaps":["Whether ERK regulation in neurons proceeds through RTK inhibition as in GBM not tested","Mechanistic link between FRMD6 and c-MYC signaling not delineated","In vivo neuronal phenotype of Frmd6 loss not assessed"]},{"year":2022,"claim":"Demonstrating that FRMD6 maintains mitochondrial morphology and function in neurons and rescues Aβ-induced mitochondrial fragmentation established a novel organelle-level function, linking FRMD6 to neurodegeneration-relevant biology.","evidence":"siRNA knockdown and overexpression in HT-22 and primary neurons, mitochondrial morphology imaging, oxygen consumption assays, Aβ peptide rescue","pmids":["36231104"],"confidence":"Medium","gaps":["Whether mitochondrial regulation is mediated through ERK, Hippo, or an independent pathway not resolved","No in vivo neuronal model tested","Single lab report"]},{"year":2023,"claim":"Two studies completed the upstream-to-downstream wiring of FRMD6: one demonstrated direct FRMD6–MST co-immunoprecipitation and placed FRMD6 downstream of p53/SMAD/TGF-β to drive senescence via YAP-regulated CCN3; the other showed FRMD6 scaffolds mTOR–S6K to activate mTOR signaling, revealing a Hippo-independent pro-growth output.","evidence":"Co-IP of FRMD6–MST, in vivo lung senescence model, TGF-β induction, CCN3 rescue (senescence); Co-IP of FRMD6–mTOR and FRMD6–S6K, KO MEFs and mice, phospho-S6K/S6 Western blots (mTOR)","pmids":["38926528","37060526"],"confidence":"High","gaps":["How FRMD6 simultaneously activates Hippo (anti-growth) and mTOR (pro-growth) in the same cell type is paradoxical and unresolved","Structural basis of FRMD6–MST and FRMD6–mTOR interactions unknown","Context-dependent switching between Hippo and mTOR arms not defined"]},{"year":2026,"claim":"Identification of FRMD6 as an upstream regulator of VE-cadherin phosphorylation and adherens junction stability in endothelial cells extended its junctional regulatory role to vascular biology and angiogenesis.","evidence":"siRNA knockdown in endothelial cells, transcriptome sequencing, VE-cadherin phosphorylation blots, in vivo rat calvarial defect model","pmids":["41916139"],"confidence":"Medium","gaps":["Direct mechanism linking FRMD6 to VE-cadherin phosphorylation not identified","Whether this proceeds through Hippo, aPKC, or a distinct pathway not distinguished"]},{"year":null,"claim":"The central unresolved question is how FRMD6 coordinates its opposing downstream outputs — Hippo-mediated growth suppression versus mTOR-mediated growth promotion — in a context-dependent manner, and what structural features or post-translational modifications govern pathway selection.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of FRMD6 or its complexes with MST, mTOR, or nectins","Post-translational modifications of FRMD6 that regulate pathway choice not characterized","In vivo genetic models for neuronal and vascular functions of FRMD6 lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,10,11]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,5,6,7,8,10,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,3,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,7]}],"complexes":[],"partners":["MST1","MST2","LATS1","PRKCI","NECTIN1","MTOR","RPS6KB1","NTRK2"],"other_free_text":[]},"mechanistic_narrative":"FRMD6 (Willin) is a FERM-domain scaffolding protein that functions as a multivalent upstream regulator of Hippo signaling, epithelial polarity, receptor tyrosine kinase activity, and mTOR signaling. FRMD6 directly binds and activates MST1/2 kinase through its N-terminal FERM domain, promoting LATS1 activation and inhibitory YAP/TAZ phosphorylation, thereby suppressing proliferation and inducing senescence; this pathway is antagonized by ezrin and regulated upstream by p53, SMADs, and TGF-β [PMID:21666719, PMID:38926528]. Independent of core Hippo kinases, FRMD6 recruits aPKC/Par6 to apical junctional complexes to suppress ROCK-dependent actomyosin contractility, localizes to junctions through direct nectin binding, inhibits RTK (c-Met/PDGFR) signaling in glioblastoma, and scaffolds the mTOR–S6K interaction to activate mTOR signaling in lung cancer cells [PMID:21685893, PMID:22512338, PMID:27661120, PMID:37060526]. In neuronal cells, FRMD6 modulates ERK1/2 signaling, promotes retinoic acid–induced differentiation, and maintains mitochondrial homeostasis, rescuing Aβ-induced mitochondrial dysfunction [PMID:33088261, PMID:36231104]."},"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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cytochalasin D treatment, EGF stimulation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple imaging/biochemical methods but no functional rescue or mutagenesis\",\n      \"pmids\": [\"16137681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Willin/FRMD6 expression activates the Hippo signaling pathway kinases MST1/2 and LATS1 and increases YAP phosphorylation in mammalian cells; this effect can be antagonized by ezrin. The N-terminal FERM domain of Willin is required to antagonize YAP activity. Loss of Willin in MCF10A cells induces epithelial-to-mesenchymal transition features.\",\n      \"method\": \"Ectopic expression in D. melanogaster and mammalian cells, phospho-Western blotting for MST1/2, LATS1, YAP; FERM domain deletion constructs; shRNA knockdown with EMT readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (phospho-WB, domain deletion, KD phenotype) in single study with clear mechanistic pathway placement\",\n      \"pmids\": [\"21666719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Willin/FRMD6 recruits aPKC and Par6 to apical junctional complexes (AJCs) independently of Par3. Simultaneous depletion of Willin and Par3 removes aPKC/Par6 from AJCs and induces apical constriction via upregulated ROCK at junctions. aPKC phosphorylates ROCK and suppresses its junctional localization, establishing a Willin/Par3–aPKC–ROCK pathway controlling epithelial apical morphology.\",\n      \"method\": \"siRNA knockdown (single and double), immunofluorescence localization, ROCK inhibitor rescue, co-immunoprecipitation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via double knockdown, rescue experiments, and direct localization with functional consequence\",\n      \"pmids\": [\"21685893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Willin/FRMD6 binds directly to nectins (Ig-family cell adhesion proteins) at apical junctional complexes; this nectin interaction mediates the junctional recruitment of Willin. Nectin positioning at AJCs depends on afadin binding to nectins.\",\n      \"method\": \"Co-immunoprecipitation, knockdown of afadin with loss-of-Willin junctional localization as readout, immunofluorescence\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus localization data from single lab\",\n      \"pmids\": [\"22512338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In mammalian sciatic nerve fibroblasts, Willin/FRMD6 expression activates the Hippo signaling cascade and induces YAP translocation from the nucleus to the cytoplasm (Ser127 phosphorylation), inhibits cellular proliferation, and promotes directional migration toward scratch closure.\",\n      \"method\": \"Overexpression, Western blotting for YAP phosphorylation, nuclear/cytoplasmic fractionation, scratch wound migration assay, proliferation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23593160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FRMD6 inhibits glioblastoma cell proliferation/invasion by suppressing activation of receptor tyrosine kinases c-Met and PDGFR and their downstream ERK and AKT kinases, rather than through the core Hippo kinase cascade. Expression of constitutively active TPR-Met largely reverses the anti-GBM effect of FRMD6 in vivo, placing FRMD6 upstream of c-Met signaling.\",\n      \"method\": \"Overexpression and knockdown in GBM cells, xenograft in vivo models, phospho-Western blotting (c-Met, PDGFR, ERK, AKT), constitutively active c-Met rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via constitutively active rescue plus phospho-proteomics, single lab\",\n      \"pmids\": [\"27661120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In aged cardiac microvascular endothelial cells, BDNF signals through the truncated TrkB-T1 receptor to recruit Willin/FRMD6 as a downstream effector, which then activates the Hippo pathway to promote cell migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, BDNF stimulation assay, migration assay\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional migration readout, single lab\",\n      \"pmids\": [\"30667167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FRMD6 overexpression inhibits prostate cancer cell viability, proliferation, colony formation, and xenograft tumor growth, while CRISPR/Cas9 knockout promotes these phenotypes and leads to enrichment of Hippo/YAP and c-MYC signaling as shown by phospho-proteomics. In vivo, Frmd6/Pten double knockout in mouse prostate causes high-grade prostatic intraepithelial neoplasia and hyperproliferation beyond that seen with Pten loss alone.\",\n      \"method\": \"Overexpression and CRISPR/Cas9 KO, xenograft growth assay, transcriptomic/proteomic/phospho-proteomic profiling, orthotropic mouse double KO model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, OE, in vivo mouse model, proteomics) with clear mechanistic pathway placement\",\n      \"pmids\": [\"33249427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Willin/FRMD6 expression in SH-SY5Y neuronal cells influences cell mechanical phenotype (cell force and actin stress fiber organization), neuronal differentiation, proliferation, and migration. Changes in Willin/FRMD6 expression inversely affect ERK1/2 signaling activity and downstream transcription factor NeuroD1, priming cells for retinoic acid-induced neuronal differentiation.\",\n      \"method\": \"Overexpression and siRNA knockdown, ERISM biophysical measurements, Western blotting for pERK1/2 and NeuroD1, neurite outgrowth and focal adhesion imaging, retinoic acid differentiation assay\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biophysical + biochemical + cellular), single lab\",\n      \"pmids\": [\"33088261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Willin/FRMD6 knockdown in mouse hippocampal HT-22 cells and primary mouse neurons leads to mitochondrial dysfunction and fragmentation, and upregulation of ERK1/2 signaling. Increased Willin/FRMD6 expression rescues Aβ-induced abnormalities in mitochondrial morphology, function, and energetics, positioning FRMD6 as a regulator of mitochondrial homeostasis in neurons.\",\n      \"method\": \"siRNA knockdown and overexpression, mitochondrial morphology imaging, mitochondrial function assays (oxygen consumption), Western blotting for pERK1/2, Aβ peptide treatment\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss and gain of function with rescue, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"36231104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FRMD6 interacts with and activates MST kinase (co-immunoprecipitation demonstrated), leading to YAP/TAZ inactivation (increased inhibitory phosphorylation). FRMD6 overexpression alone induces senescence in cells and lung tissue, while FRMD6 silencing mitigates senescence. The downstream secretory factor CCN3 (regulated by YAP) can rescue FRMD6-induced senescence. FRMD6 expression is regulated upstream by p53 and SMAD transcription factors and is induced by TGF-β.\",\n      \"method\": \"Co-immunoprecipitation (FRMD6-MST interaction), overexpression and siRNA knockdown, phospho-Western blotting (YAP/TAZ), in vivo lung senescence model, proteomic analysis, TGF-β treatment, CCN3 rescue experiment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP of FRMD6-MST interaction plus multiple orthogonal functional methods and in vivo model with clear mechanistic pathway\",\n      \"pmids\": [\"38926528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FRMD6 interacts and colocalizes with mTOR and S6K, and markedly enhances the interaction between mTOR and S6K, increasing levels of phospho-S6K and downstream phospho-S6 in lung cancer cells. Knockout of FRMD6 inhibits mTOR pathway activation in MEFs and mice, establishing FRMD6 as an activator of mTOR signaling in lung cancer.\",\n      \"method\": \"Co-immunoprecipitation (FRMD6-mTOR, FRMD6-S6K), colocalization imaging, phospho-Western blotting (pS6K, pS6), FRMD6 knockout MEFs and mice\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo KO validation, single lab\",\n      \"pmids\": [\"37060526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FRMD6 knockdown in endothelial cells restores adherens junction (AJ) stability and abolishes Si3N4 nanoparticle-mediated pro-angiogenic effects. FRMD6 was identified as the most significantly upregulated upstream regulator mediating Si3N4 NP-induced phosphorylation of VE-cadherin and AJ dissociation, establishing FRMD6 as an upstream regulator of VE-cadherin phosphorylation in angiogenesis.\",\n      \"method\": \"siRNA knockdown, transcriptome sequencing, Western blotting for VE-cadherin phosphorylation, in vivo rat calvarial defect model with local FRMD6 knockdown\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with functional rescue in vivo and in vitro with defined molecular target, single lab\",\n      \"pmids\": [\"41916139\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRMD6/Willin is a FERM-domain protein that functions as an upstream activator of the Hippo signaling pathway by directly binding and activating MST kinase to promote YAP/TAZ phosphorylation and cytoplasmic sequestration; it also recruits aPKC to apical junctional complexes to suppress ROCK-dependent actomyosin contractility, interacts with nectins for junctional localization, inhibits RTK (c-Met, PDGFR) and promotes ERK signaling in neuronal cells, activates the mTOR pathway by scaffolding mTOR-S6K interactions, regulates mitochondrial homeostasis, and acts downstream of TrkB-T1/BDNF signaling to promote cell migration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FRMD6 (Willin) is a FERM-domain scaffolding protein that functions as a multivalent upstream regulator of Hippo signaling, epithelial polarity, receptor tyrosine kinase activity, and mTOR signaling. FRMD6 directly binds and activates MST1/2 kinase through its N-terminal FERM domain, promoting LATS1 activation and inhibitory YAP/TAZ phosphorylation, thereby suppressing proliferation and inducing senescence; this pathway is antagonized by ezrin and regulated upstream by p53, SMADs, and TGF-β [PMID:21666719, PMID:38926528]. Independent of core Hippo kinases, FRMD6 recruits aPKC/Par6 to apical junctional complexes to suppress ROCK-dependent actomyosin contractility, localizes to junctions through direct nectin binding, inhibits RTK (c-Met/PDGFR) signaling in glioblastoma, and scaffolds the mTOR–S6K interaction to activate mTOR signaling in lung cancer cells [PMID:21685893, PMID:22512338, PMID:27661120, PMID:37060526]. In neuronal cells, FRMD6 modulates ERK1/2 signaling, promotes retinoic acid–induced differentiation, and maintains mitochondrial homeostasis, rescuing Aβ-induced mitochondrial dysfunction [PMID:33088261, PMID:36231104].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing FRMD6 as a FERM-domain-containing, phospholipid-binding protein that localizes to the plasma membrane independently of actin, answering the basic question of its domain architecture and subcellular targeting.\",\n      \"evidence\": \"Subcellular fractionation, co-localization imaging, cytochalasin D and EGF stimulation in cultured cells\",\n      \"pmids\": [\"16137681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional consequence of membrane localization was demonstrated\",\n        \"Phospholipid binding specificity not mapped to specific lipid species\",\n        \"Single lab characterization without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies established FRMD6 as a dual regulator of epithelial cell biology: one showed it activates the Hippo kinase cascade (MST→LATS→pYAP) via its FERM domain, while the other demonstrated it recruits aPKC/Par6 to apical junctions to suppress ROCK-mediated apical constriction, answering how FRMD6 controls both proliferation and cell shape.\",\n      \"evidence\": \"Phospho-Western blotting of MST/LATS/YAP, FERM domain deletion, shRNA-induced EMT (Hippo); siRNA double knockdown, ROCK inhibitor rescue, co-IP (aPKC/Par6 pathway)\",\n      \"pmids\": [\"21666719\", \"21685893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Hippo activation and aPKC recruitment are mechanistically linked or independent functions\",\n        \"No structural basis for FERM domain–MST interaction\",\n        \"Endogenous stoichiometry of FRMD6 at junctions not determined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying nectins as direct binding partners that recruit FRMD6 to apical junctional complexes answered how FRMD6 is positioned at cell–cell contacts to exert its polarity and signaling functions.\",\n      \"evidence\": \"Co-immunoprecipitation of FRMD6–nectin, afadin knockdown abolishing junctional FRMD6 localization\",\n      \"pmids\": [\"22512338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding interface between nectin and FRMD6 FERM domain not mapped\",\n        \"Single Co-IP study without reciprocal pull-down validation reported\",\n        \"Whether nectin binding is required for Hippo activation not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating FRMD6-mediated YAP phosphorylation and nuclear exclusion in sciatic nerve fibroblasts extended Hippo activation beyond epithelial cells and linked it to migration and growth control in mesenchymal contexts.\",\n      \"evidence\": \"Overexpression with nuclear/cytoplasmic fractionation, scratch wound and proliferation assays in sciatic nerve fibroblasts\",\n      \"pmids\": [\"23593160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Loss-of-function data in these cells not provided\",\n        \"Mechanism linking Hippo activation to directional migration not defined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealing that FRMD6 suppresses glioblastoma growth by inhibiting c-Met and PDGFR activation rather than through canonical Hippo kinases established a Hippo-independent tumor-suppressive mechanism and broadened FRMD6's signaling repertoire.\",\n      \"evidence\": \"Overexpression/knockdown in GBM cells, xenograft models, constitutively active TPR-Met rescue reversing FRMD6 anti-tumor effects\",\n      \"pmids\": [\"27661120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between FRMD6 and RTKs not shown\",\n        \"How FRMD6 inhibits RTK activation mechanistically remains undefined\",\n        \"Single lab without independent replication in other GBM models\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placing FRMD6 downstream of BDNF/TrkB-T1 signaling in aged cardiac endothelial cells identified a receptor-level input that activates FRMD6 to promote Hippo-dependent migration, answering how FRMD6 is engaged by extracellular signals.\",\n      \"evidence\": \"Co-immunoprecipitation of TrkB-T1–FRMD6, siRNA knockdown, BDNF stimulation and migration assays in aged cardiac microvascular endothelial cells\",\n      \"pmids\": [\"30667167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus adaptor-mediated interaction with TrkB-T1 not distinguished\",\n        \"Relevance to in vivo cardiac aging not validated genetically\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies expanded FRMD6's roles in cancer suppression and neuronal biology: CRISPR knockout in prostate cancer with in vivo double-KO mouse models confirmed tumor-suppressive function through Hippo/YAP and c-MYC, while neuronal studies showed FRMD6 modulates cell mechanics, ERK signaling, and NeuroD1-dependent differentiation.\",\n      \"evidence\": \"CRISPR KO, xenografts, Frmd6/Pten double-KO mouse prostate model, phospho-proteomics (prostate cancer); overexpression/knockdown with ERISM biophysics, pERK/NeuroD1 Western blots, retinoic acid differentiation (neuronal cells)\",\n      \"pmids\": [\"33249427\", \"33088261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ERK regulation in neurons proceeds through RTK inhibition as in GBM not tested\",\n        \"Mechanistic link between FRMD6 and c-MYC signaling not delineated\",\n        \"In vivo neuronal phenotype of Frmd6 loss not assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that FRMD6 maintains mitochondrial morphology and function in neurons and rescues Aβ-induced mitochondrial fragmentation established a novel organelle-level function, linking FRMD6 to neurodegeneration-relevant biology.\",\n      \"evidence\": \"siRNA knockdown and overexpression in HT-22 and primary neurons, mitochondrial morphology imaging, oxygen consumption assays, Aβ peptide rescue\",\n      \"pmids\": [\"36231104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether mitochondrial regulation is mediated through ERK, Hippo, or an independent pathway not resolved\",\n        \"No in vivo neuronal model tested\",\n        \"Single lab report\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies completed the upstream-to-downstream wiring of FRMD6: one demonstrated direct FRMD6–MST co-immunoprecipitation and placed FRMD6 downstream of p53/SMAD/TGF-β to drive senescence via YAP-regulated CCN3; the other showed FRMD6 scaffolds mTOR–S6K to activate mTOR signaling, revealing a Hippo-independent pro-growth output.\",\n      \"evidence\": \"Co-IP of FRMD6–MST, in vivo lung senescence model, TGF-β induction, CCN3 rescue (senescence); Co-IP of FRMD6–mTOR and FRMD6–S6K, KO MEFs and mice, phospho-S6K/S6 Western blots (mTOR)\",\n      \"pmids\": [\"38926528\", \"37060526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How FRMD6 simultaneously activates Hippo (anti-growth) and mTOR (pro-growth) in the same cell type is paradoxical and unresolved\",\n        \"Structural basis of FRMD6–MST and FRMD6–mTOR interactions unknown\",\n        \"Context-dependent switching between Hippo and mTOR arms not defined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of FRMD6 as an upstream regulator of VE-cadherin phosphorylation and adherens junction stability in endothelial cells extended its junctional regulatory role to vascular biology and angiogenesis.\",\n      \"evidence\": \"siRNA knockdown in endothelial cells, transcriptome sequencing, VE-cadherin phosphorylation blots, in vivo rat calvarial defect model\",\n      \"pmids\": [\"41916139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism linking FRMD6 to VE-cadherin phosphorylation not identified\",\n        \"Whether this proceeds through Hippo, aPKC, or a distinct pathway not distinguished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is how FRMD6 coordinates its opposing downstream outputs — Hippo-mediated growth suppression versus mTOR-mediated growth promotion — in a context-dependent manner, and what structural features or post-translational modifications govern pathway selection.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of FRMD6 or its complexes with MST, mTOR, or nectins\",\n        \"Post-translational modifications of FRMD6 that regulate pathway choice not characterized\",\n        \"In vivo genetic models for neuronal and vascular functions of FRMD6 lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 5, 6, 7, 8, 10, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MST1\",\n      \"MST2\",\n      \"LATS1\",\n      \"PRKCI\",\n      \"NECTIN1\",\n      \"MTOR\",\n      \"RPS6KB1\",\n      \"NTRK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}