{"gene":"FRMD5","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2012,"finding":"FRMD5 localizes at cell adherens junctions and forms a molecular complex with p120-catenin through its C-terminal region; knockdown of endogenous FRMD5 promotes lung cancer cell migration and invasion in vitro and tumor growth in vivo, indicating a tumor-suppressive role linked to p120-catenin-based cell-cell contact.","method":"Co-immunoprecipitation, domain mapping (C-terminal truncation), siRNA knockdown with migration/invasion assays and in vivo tumor growth assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal complex formation identified by Co-IP with domain mapping, functional knockdown phenotype, but single lab","pmids":["22846708"],"is_preprint":false},{"year":2014,"finding":"FRMD5 regulates cell migration via a dual mechanism: (1) it binds directly to the integrin β5 cytoplasmic tail, promoting cell-matrix adhesion and spreading on vitronectin; and (2) it interacts with ROCK1 and inhibits its activation, thereby reducing myosin light chain phosphorylation and actin stress fiber formation.","method":"Co-immunoprecipitation, pulldown assays, siRNA knockdown, cell migration assays, myosin light chain phosphorylation assay, actin staining","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding partners identified by Co-IP/pulldown with multiple orthogonal functional readouts, single lab","pmids":["25448675"],"is_preprint":false},{"year":2018,"finding":"FRMD5 is a downstream transcriptional/stabilization target of a Cav1/LRP6/β-catenin signaling axis driven by C-terminally truncated HBx (HBxΔC); constitutively active β-catenin in Cav1-knockdown cells rescues FRMD5 expression and HCC tumorigenesis/metastasis, placing FRMD5 downstream of β-catenin in this pathway.","method":"Expression profiling, siRNA knockdown, constitutively active β-catenin rescue experiment, Western blot, in vivo tumorigenesis assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiment and knockdown, multiple functional readouts, single lab","pmids":["30583072"],"is_preprint":false},{"year":2022,"finding":"The Drosophila ortholog of FRMD5 (dFrmd/CG5022) is expressed in neurons (but not glia) of the larval and adult CNS; loss-of-function mutants show severe heat-shock-induced seizures and defective light responses. Human FRMD5 reference cDNA rescues these phenotypes, while six disease-associated missense variants tested behave as partial loss-of-function, and two additionally show dominant-negative effects.","method":"Drosophila genetics (LoF mutants), neuronal expression analysis, human cDNA rescue, variant functional testing in fly model, behavioral assays (seizure susceptibility, light response)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthologous rescue with human cDNA plus variant-specific functional testing in vivo; multiple variants tested with two orthogonal phenotypic readouts, replicated across six variants","pmids":["36206744"],"is_preprint":false},{"year":2024,"finding":"FRMD5 deficiency in mice (Frmd5 knockout) causes morphological abnormalities in neurons and synaptic dysfunction; TMT quantitative proteomics revealed altered distribution of synaptic proteins involved in ASD pathology, linking FRMD5's scaffolding function to synapse maintenance and neurodevelopment.","method":"Frmd5 knockout mouse model, behavioral assays (learning/memory, social function, repetitive behavior), neuromorphological analysis, TMT-labeled quantitative proteomics of synaptic proteins","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined cellular/synaptic phenotype and proteomics pathway placement, single lab","pmids":["38228891"],"is_preprint":false},{"year":2026,"finding":"FRMD5 interacts with JAK2 and STAT3, enhancing JAK2/STAT3 complex formation and promoting STAT3 phosphorylation; urinary epithelium-specific knockout of Frmd5 in mice inactivates the JAK2-STAT3 pathway, reduces epithelial apoptosis (decreased Casp3, Casp8; increased Bcl2, Bcl-XL), and causes failure of vaginal lumen formation with infertility.","method":"Co-immunoprecipitation (Frmd5 with Jak2 and Stat3), conditional knockout mouse (Cdh16-Cre), phospho-STAT3 assay, qPCR of apoptotic genes, vaginal morphology assessment","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction identified by Co-IP with in vivo conditional KO demonstrating pathway inactivation and defined developmental phenotype, multiple orthogonal methods","pmids":["42003911"],"is_preprint":false}],"current_model":"FRMD5 is a FERM domain-containing scaffolding protein that localizes to cell adherens junctions where it interacts with p120-catenin (via its C-terminal region), integrin β5 (promoting cell-matrix adhesion), and ROCK1 (inhibiting its activation and downstream myosin light chain phosphorylation and actin stress fiber formation) to suppress cell migration and invasion; it also interacts with JAK2 and STAT3 to enhance JAK2/STAT3 complex formation and STAT3 phosphorylation, which is required for epithelial apoptosis during vaginal lumen formation; in neurons, FRMD5 acts as a synaptic scaffolding protein whose loss disrupts synaptic protein distribution and causes neurodevelopmental defects, with disease-associated missense variants behaving as partial loss-of-function or dominant-negative alleles in vivo."},"narrative":{"mechanistic_narrative":"FRMD5 is a FERM domain-containing scaffolding protein that controls cell adhesion and motility at junctional and adhesive contacts and that supports neuronal and epithelial developmental programs [PMID:22846708, PMID:36206744]. At adherens junctions it forms a complex with p120-catenin through its C-terminal region, and its loss promotes cancer cell migration, invasion, and tumor growth, defining a tumor-suppressive role tied to cell-cell contact [PMID:22846708]. It additionally couples cell-matrix and cytoskeletal control by binding directly to the integrin β5 cytoplasmic tail to promote spreading on vitronectin while interacting with ROCK1 to inhibit its activation, thereby restraining myosin light chain phosphorylation and actin stress fiber formation [PMID:25448675]. Beyond adhesion, FRMD5 acts as a signaling scaffold that binds JAK2 and STAT3, enhances JAK2/STAT3 complex assembly and STAT3 phosphorylation, and thereby drives epithelial apoptosis required for vaginal lumen formation in vivo [PMID:42003911]. In the nervous system FRMD5 is a neuron-expressed synaptic scaffold whose loss disrupts neuronal morphology and the distribution of synaptic proteins, and disease-associated missense variants behave as partial loss-of-function or dominant-negative alleles in a rescue-based fly model, establishing FRMD5 as a neurodevelopmental disease gene [PMID:36206744, PMID:38228891].","teleology":[{"year":2012,"claim":"Established the first molecular function of FRMD5 by placing it at adherens junctions in a complex with p120-catenin and linking it to suppression of tumor cell motility.","evidence":"Co-IP with C-terminal domain mapping plus siRNA knockdown with migration/invasion and in vivo tumor assays in lung cancer cells","pmids":["22846708"],"confidence":"Medium","gaps":["Single lab; structural basis of the FRMD5–p120-catenin interaction undefined","Whether junctional localization requires the FERM domain not resolved"]},{"year":2014,"claim":"Extended FRMD5 function from cell-cell contacts to cell-matrix adhesion and cytoskeletal control by identifying direct integrin β5 and ROCK1 binding.","evidence":"Co-IP/pulldown, siRNA knockdown, migration assays, MLC phosphorylation and actin staining","pmids":["25448675"],"confidence":"Medium","gaps":["Mechanism by which FRMD5 inhibits ROCK1 activation not defined","Single lab; relationship between integrin and ROCK1 arms of the mechanism unresolved"]},{"year":2018,"claim":"Positioned FRMD5 within a signaling cascade by showing its expression is regulated downstream of a Cav1/LRP6/β-catenin axis in hepatocellular carcinoma.","evidence":"Expression profiling, knockdown, constitutively active β-catenin rescue, Western blot and in vivo tumorigenesis","pmids":["30583072"],"confidence":"Medium","gaps":["Whether FRMD5 is a direct transcriptional target or stabilized post-translationally not distinguished","Single lab; functional output of FRMD5 in this axis not mechanistically dissected"]},{"year":2022,"claim":"Defined FRMD5 as a neuronal gene whose dysfunction causes disease, using orthologous rescue and variant testing to demonstrate that patient missense alleles are partial loss-of-function or dominant-negative.","evidence":"Drosophila LoF mutants, human cDNA rescue, six variant functional tests, seizure and light-response behavioral assays","pmids":["36206744"],"confidence":"High","gaps":["Molecular function disrupted in neurons not identified at the protein level","Human partners mediating the neuronal role not mapped in this system"]},{"year":2024,"claim":"Identified the cellular basis of FRMD5's neuronal role by showing knockout disrupts neuronal morphology and synaptic protein distribution relevant to ASD pathology.","evidence":"Frmd5 knockout mouse with behavioral assays, neuromorphology, and TMT quantitative synaptic proteomics","pmids":["38228891"],"confidence":"Medium","gaps":["Direct synaptic binding partners of FRMD5 not established","Single lab; mechanistic link between altered protein distribution and behavior not defined"]},{"year":2026,"claim":"Revealed a distinct signaling-scaffold function by showing FRMD5 binds JAK2 and STAT3 to promote pathway activation and epithelial apoptosis during organ morphogenesis.","evidence":"Co-IP of Frmd5 with Jak2/Stat3, Cdh16-Cre conditional KO, phospho-STAT3, apoptotic gene qPCR, vaginal morphology","pmids":["42003911"],"confidence":"High","gaps":["Domain of FRMD5 mediating JAK2/STAT3 binding not mapped","Whether this scaffolding role intersects with its adhesion functions unknown"]},{"year":null,"claim":"How the FERM domain and C-terminal region of FRMD5 are partitioned across its adhesion, cytoskeletal, JAK2/STAT3, and synaptic scaffolding roles, and whether these reflect one unified biochemical activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FRMD5 or its complexes","Domain requirements for the JAK2/STAT3 and synaptic functions not mapped","Unifying molecular activity across cell types not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4]}],"complexes":[],"partners":["CTNND1","ITGB5","ROCK1","JAK2","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z6J6","full_name":"FERM domain-containing protein 5","aliases":[],"length_aa":570,"mass_kda":65.1,"function":"May be involved in regulation of cell migration (PubMed:22846708, PubMed:25448675). May regulate cell-matrix interactions via its interaction with ITGB5 and modifying ITGB5 cytoplasmic tail interactions such as with FERMT2 and TLN1. May regulate ROCK1 kinase activity possibly involved in regulation of actin stress fiber formation (PubMed:25448675)","subcellular_location":"Membrane; Cell junction, adherens junction","url":"https://www.uniprot.org/uniprotkb/Q7Z6J6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRMD5","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/FRMD5","total_profiled":1310},"omim":[{"mim_id":"620094","title":"NEURODEVELOPMENTAL DISORDER WITH EYE MOVEMENT ABNORMALITIES AND ATAXIA; NEDEMA","url":"https://www.omim.org/entry/620094"},{"mim_id":"616309","title":"FERM DOMAIN-CONTAINING PROTEIN 5; FRMD5","url":"https://www.omim.org/entry/616309"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":17.5},{"tissue":"heart muscle","ntpm":43.6},{"tissue":"retina","ntpm":18.5}],"url":"https://www.proteinatlas.org/search/FRMD5"},"hgnc":{"alias_symbol":["MGC14161"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z6J6","domains":[{"cath_id":"3.10.20.90","chopping":"13-93","consensus_level":"high","plddt":91.3062,"start":13,"end":93},{"cath_id":"1.20.80.10","chopping":"121-126_128-199","consensus_level":"high","plddt":91.6199,"start":121,"end":199},{"cath_id":"2.30.29.30","chopping":"209-331","consensus_level":"high","plddt":91.7807,"start":209,"end":331},{"cath_id":"-","chopping":"504-568","consensus_level":"medium","plddt":83.9294,"start":504,"end":568}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z6J6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z6J6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z6J6-F1-predicted_aligned_error_v6.png","plddt_mean":74.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRMD5","jax_strain_url":"https://www.jax.org/strain/search?query=FRMD5"},"sequence":{"accession":"Q7Z6J6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z6J6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z6J6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z6J6"}},"corpus_meta":[{"pmid":"30583072","id":"PMC_30583072","title":"C-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30583072","citation_count":28,"is_preprint":false},{"pmid":"22846708","id":"PMC_22846708","title":"FERM-containing protein FRMD5 is a p120-catenin interacting protein that regulates tumor progression.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22846708","citation_count":26,"is_preprint":false},{"pmid":"25448675","id":"PMC_25448675","title":"FERM domain-containing protein FRMD5 regulates cell motility via binding to integrin β5 subunit and ROCK1.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25448675","citation_count":23,"is_preprint":false},{"pmid":"36206744","id":"PMC_36206744","title":"De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36206744","citation_count":21,"is_preprint":false},{"pmid":"38228891","id":"PMC_38228891","title":"Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice.","date":"2024","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38228891","citation_count":9,"is_preprint":false},{"pmid":"34201607","id":"PMC_34201607","title":"Analysis of the Role of FRMD5 in the Biology of Papillary Thyroid Carcinoma.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34201607","citation_count":8,"is_preprint":false},{"pmid":"38576116","id":"PMC_38576116","title":"De novo FRMD5 Missense Variants in Patients with Childhood-Onset Ataxia, Prominent Nystagmus, and Seizures.","date":"2024","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/38576116","citation_count":2,"is_preprint":false},{"pmid":"39980901","id":"PMC_39980901","title":"Neonatal-Onset Opsoclonus-Myoclonus-Ataxia-Like Syndrome Caused by De Novo FRMD5 Variant Responsive to IV Steroid Pulse Therapy: Case Report.","date":"2025","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39980901","citation_count":0,"is_preprint":false},{"pmid":"39583022","id":"PMC_39583022","title":"A Novel Type of Autosomal Dominant Episodic Nystagmus Segregating with a Variant in the FRMD5 Gene.","date":"2024","source":"Neuro-ophthalmology (Aeolus Press)","url":"https://pubmed.ncbi.nlm.nih.gov/39583022","citation_count":0,"is_preprint":false},{"pmid":"42003911","id":"PMC_42003911","title":"Loss of Frmd5 Inhibits Jak2-Stat3 Signalling Pathway and Impairs Cell Apoptosis During Vagina Luminal Formation in Puberty Mice.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42003911","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6888,"output_tokens":1730,"usd":0.023307,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8633,"output_tokens":2545,"usd":0.053395,"stage2_stop_reason":"end_turn"},"total_usd":0.076702,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"FRMD5 localizes at cell adherens junctions and forms a molecular complex with p120-catenin through its C-terminal region; knockdown of endogenous FRMD5 promotes lung cancer cell migration and invasion in vitro and tumor growth in vivo, indicating a tumor-suppressive role linked to p120-catenin-based cell-cell contact.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (C-terminal truncation), siRNA knockdown with migration/invasion assays and in vivo tumor growth assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal complex formation identified by Co-IP with domain mapping, functional knockdown phenotype, but single lab\",\n      \"pmids\": [\"22846708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FRMD5 regulates cell migration via a dual mechanism: (1) it binds directly to the integrin β5 cytoplasmic tail, promoting cell-matrix adhesion and spreading on vitronectin; and (2) it interacts with ROCK1 and inhibits its activation, thereby reducing myosin light chain phosphorylation and actin stress fiber formation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, siRNA knockdown, cell migration assays, myosin light chain phosphorylation assay, actin staining\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding partners identified by Co-IP/pulldown with multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"25448675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FRMD5 is a downstream transcriptional/stabilization target of a Cav1/LRP6/β-catenin signaling axis driven by C-terminally truncated HBx (HBxΔC); constitutively active β-catenin in Cav1-knockdown cells rescues FRMD5 expression and HCC tumorigenesis/metastasis, placing FRMD5 downstream of β-catenin in this pathway.\",\n      \"method\": \"Expression profiling, siRNA knockdown, constitutively active β-catenin rescue experiment, Western blot, in vivo tumorigenesis assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiment and knockdown, multiple functional readouts, single lab\",\n      \"pmids\": [\"30583072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The Drosophila ortholog of FRMD5 (dFrmd/CG5022) is expressed in neurons (but not glia) of the larval and adult CNS; loss-of-function mutants show severe heat-shock-induced seizures and defective light responses. Human FRMD5 reference cDNA rescues these phenotypes, while six disease-associated missense variants tested behave as partial loss-of-function, and two additionally show dominant-negative effects.\",\n      \"method\": \"Drosophila genetics (LoF mutants), neuronal expression analysis, human cDNA rescue, variant functional testing in fly model, behavioral assays (seizure susceptibility, light response)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthologous rescue with human cDNA plus variant-specific functional testing in vivo; multiple variants tested with two orthogonal phenotypic readouts, replicated across six variants\",\n      \"pmids\": [\"36206744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FRMD5 deficiency in mice (Frmd5 knockout) causes morphological abnormalities in neurons and synaptic dysfunction; TMT quantitative proteomics revealed altered distribution of synaptic proteins involved in ASD pathology, linking FRMD5's scaffolding function to synapse maintenance and neurodevelopment.\",\n      \"method\": \"Frmd5 knockout mouse model, behavioral assays (learning/memory, social function, repetitive behavior), neuromorphological analysis, TMT-labeled quantitative proteomics of synaptic proteins\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined cellular/synaptic phenotype and proteomics pathway placement, single lab\",\n      \"pmids\": [\"38228891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FRMD5 interacts with JAK2 and STAT3, enhancing JAK2/STAT3 complex formation and promoting STAT3 phosphorylation; urinary epithelium-specific knockout of Frmd5 in mice inactivates the JAK2-STAT3 pathway, reduces epithelial apoptosis (decreased Casp3, Casp8; increased Bcl2, Bcl-XL), and causes failure of vaginal lumen formation with infertility.\",\n      \"method\": \"Co-immunoprecipitation (Frmd5 with Jak2 and Stat3), conditional knockout mouse (Cdh16-Cre), phospho-STAT3 assay, qPCR of apoptotic genes, vaginal morphology assessment\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction identified by Co-IP with in vivo conditional KO demonstrating pathway inactivation and defined developmental phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"42003911\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRMD5 is a FERM domain-containing scaffolding protein that localizes to cell adherens junctions where it interacts with p120-catenin (via its C-terminal region), integrin β5 (promoting cell-matrix adhesion), and ROCK1 (inhibiting its activation and downstream myosin light chain phosphorylation and actin stress fiber formation) to suppress cell migration and invasion; it also interacts with JAK2 and STAT3 to enhance JAK2/STAT3 complex formation and STAT3 phosphorylation, which is required for epithelial apoptosis during vaginal lumen formation; in neurons, FRMD5 acts as a synaptic scaffolding protein whose loss disrupts synaptic protein distribution and causes neurodevelopmental defects, with disease-associated missense variants behaving as partial loss-of-function or dominant-negative alleles in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRMD5 is a FERM domain-containing scaffolding protein that controls cell adhesion and motility at junctional and adhesive contacts and that supports neuronal and epithelial developmental programs [#0, #3]. At adherens junctions it forms a complex with p120-catenin through its C-terminal region, and its loss promotes cancer cell migration, invasion, and tumor growth, defining a tumor-suppressive role tied to cell-cell contact [#0]. It additionally couples cell-matrix and cytoskeletal control by binding directly to the integrin \\u03b25 cytoplasmic tail to promote spreading on vitronectin while interacting with ROCK1 to inhibit its activation, thereby restraining myosin light chain phosphorylation and actin stress fiber formation [#1]. Beyond adhesion, FRMD5 acts as a signaling scaffold that binds JAK2 and STAT3, enhances JAK2/STAT3 complex assembly and STAT3 phosphorylation, and thereby drives epithelial apoptosis required for vaginal lumen formation in vivo [#5]. In the nervous system FRMD5 is a neuron-expressed synaptic scaffold whose loss disrupts neuronal morphology and the distribution of synaptic proteins, and disease-associated missense variants behave as partial loss-of-function or dominant-negative alleles in a rescue-based fly model, establishing FRMD5 as a neurodevelopmental disease gene [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the first molecular function of FRMD5 by placing it at adherens junctions in a complex with p120-catenin and linking it to suppression of tumor cell motility.\",\n      \"evidence\": \"Co-IP with C-terminal domain mapping plus siRNA knockdown with migration/invasion and in vivo tumor assays in lung cancer cells\",\n      \"pmids\": [\"22846708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of the FRMD5\\u2013p120-catenin interaction undefined\", \"Whether junctional localization requires the FERM domain not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended FRMD5 function from cell-cell contacts to cell-matrix adhesion and cytoskeletal control by identifying direct integrin \\u03b25 and ROCK1 binding.\",\n      \"evidence\": \"Co-IP/pulldown, siRNA knockdown, migration assays, MLC phosphorylation and actin staining\",\n      \"pmids\": [\"25448675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FRMD5 inhibits ROCK1 activation not defined\", \"Single lab; relationship between integrin and ROCK1 arms of the mechanism unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned FRMD5 within a signaling cascade by showing its expression is regulated downstream of a Cav1/LRP6/\\u03b2-catenin axis in hepatocellular carcinoma.\",\n      \"evidence\": \"Expression profiling, knockdown, constitutively active \\u03b2-catenin rescue, Western blot and in vivo tumorigenesis\",\n      \"pmids\": [\"30583072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FRMD5 is a direct transcriptional target or stabilized post-translationally not distinguished\", \"Single lab; functional output of FRMD5 in this axis not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined FRMD5 as a neuronal gene whose dysfunction causes disease, using orthologous rescue and variant testing to demonstrate that patient missense alleles are partial loss-of-function or dominant-negative.\",\n      \"evidence\": \"Drosophila LoF mutants, human cDNA rescue, six variant functional tests, seizure and light-response behavioral assays\",\n      \"pmids\": [\"36206744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function disrupted in neurons not identified at the protein level\", \"Human partners mediating the neuronal role not mapped in this system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the cellular basis of FRMD5's neuronal role by showing knockout disrupts neuronal morphology and synaptic protein distribution relevant to ASD pathology.\",\n      \"evidence\": \"Frmd5 knockout mouse with behavioral assays, neuromorphology, and TMT quantitative synaptic proteomics\",\n      \"pmids\": [\"38228891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct synaptic binding partners of FRMD5 not established\", \"Single lab; mechanistic link between altered protein distribution and behavior not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a distinct signaling-scaffold function by showing FRMD5 binds JAK2 and STAT3 to promote pathway activation and epithelial apoptosis during organ morphogenesis.\",\n      \"evidence\": \"Co-IP of Frmd5 with Jak2/Stat3, Cdh16-Cre conditional KO, phospho-STAT3, apoptotic gene qPCR, vaginal morphology\",\n      \"pmids\": [\"42003911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain of FRMD5 mediating JAK2/STAT3 binding not mapped\", \"Whether this scaffolding role intersects with its adhesion functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the FERM domain and C-terminal region of FRMD5 are partitioned across its adhesion, cytoskeletal, JAK2/STAT3, and synaptic scaffolding roles, and whether these reflect one unified biochemical activity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FRMD5 or its complexes\", \"Domain requirements for the JAK2/STAT3 and synaptic functions not mapped\", \"Unifying molecular activity across cell types not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTNND1\", \"ITGB5\", \"ROCK1\", \"JAK2\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}