{"gene":"FRYL","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2005,"finding":"AF4p12 (FRYL) was identified as a novel MLL fusion partner resulting from t(4;11)(p12;q23) translocation in leukemia. The COOH-terminal part of AF4p12 fused to MLL contains a leucine zipper motif and exhibits transcriptional activation properties when fused to Gal4 DNA-binding domains in transient transfection assays, suggesting the AF4p12 fragment contributes to oncogenic activation of MLL.","method":"Cloning of fusion transcript, domain analysis, transient transfection transcriptional activation assay with Gal4 fusion constructs","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (transcriptional activation) with domain identification, single lab, two orthogonal methods (fusion cloning + Gal4 reporter)","pmids":["16061630"],"is_preprint":false},{"year":2012,"finding":"FRYL (AF4p12) was identified as a component of the NOTCH1 nuclear activation complex in T-ALL cells, where it functions as a transcription coactivator alongside the PBAF nucleosome remodeling complex and histone demethylases LSD1 and PHF8 at Notch-target genes.","method":"Immunoaffinity purification of NOTCH1 nuclear partners from T-ALL cells (mass spectrometry-based interactome)","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunoaffinity purification/MS identifying FRYL as a NOTCH1 partner, large interactome study but specifically validated the complex composition; single lab","pmids":["23022380"],"is_preprint":false},{"year":2017,"finding":"FRYL functions as a coactivator in the JAG/NOTCH signaling pathway to control expression of soluble guanylyl cyclase (sGC, encoded by GUCY1A3/GUCY1B3) in arterial smooth muscle cells. Gain- and loss-of-function experiments demonstrated that JAG/NOTCH signaling controls sGC expression together with MAML2 and FRYL, and FRYL expression was reduced in hypertension models.","method":"Gain- and loss-of-function experiments (overexpression and knockdown) in vascular cells, Western blotting, analysis of transcription factor binding motifs, gene expression analysis in angiotensin II-treated mice and hypertensive rats","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain/loss-of-function experiments with defined molecular readout (sGC expression), single lab, multiple orthogonal approaches","pmids":["28465505"],"is_preprint":false},{"year":2018,"finding":"FRYL (Fryl) was isolated as a binding partner of the Ldb1-Lhx1 transcription factor complex by tandem-affinity purification in Xenopus, indicating FRYL can associate with this LIM-homeodomain transcriptional complex.","method":"Tandem-affinity purification of Lhx1-associated proteins","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/TAP experiment identifying interaction, single lab, no functional follow-up specifically for FRYL (study focused on FRY paralog)","pmids":["30375416"],"is_preprint":false},{"year":2018,"finding":"Fryl knockout mice (null mutation by gene trapping) die soon after birth; rare survivors develop hydronephrosis and die before age 1. Fryl is expressed in renal tubular tissues (glomeruli, convoluted and collecting tubules), and Fryl-/- neonates show abnormal lining cell detachments in collecting and convoluted tubules, establishing a required role for Fryl in kidney tubular development and maintenance.","method":"Gene-trap null mouse generation, histopathological analysis, tissue expression analysis (RT-PCR/immunostaining)","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined morphological phenotype and tissue expression localization, single lab, two orthogonal methods (histology + expression)","pmids":["29409347"],"is_preprint":false},{"year":2018,"finding":"Deletion of the auto-inhibitory activation segment of human NDR1 kinase causes a marked increase in association with the Furry scaffold (FRYL), indicating FRYL preferentially interacts with an activated/open conformation of NDR1.","method":"Crystal structure of NDR1 kinase domain; mutagenesis of activation segment; co-immunoprecipitation to assess Furry scaffold interaction","journal":"Structure","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — crystal structure plus mutagenesis plus binding assay in single study; interaction with FRYL based on co-IP of deletion mutant, single lab","pmids":["29983373"],"is_preprint":false},{"year":2021,"finding":"miR-1205 directly targets FRYL, as demonstrated by identification and validation of FRYL as a direct molecular target of miR-1205 in prostate cancer cells. FRYL is overexpressed in prostate cancer cells and tissues. However, FRYL knockdown did not reduce neuroendocrine differentiation (NED), showing that miR-1205 induces NED independently of FRYL.","method":"miRNA target prediction and validation (luciferase reporter assay implied), FRYL knockdown in NED induction assay, expression analysis in cell lines and tissues","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation with knockdown and defined readout; negative result for NED is also experimentally established; single lab","pmids":["34386489"],"is_preprint":false},{"year":2019,"finding":"FRYL was identified as a binding partner of NHLRC2 by immunoprecipitation in macrophages, along with EIF2AK2 and KLHL13.","method":"Immunoprecipitation of NHLRC2 followed by identification of FRYL as interacting protein","journal":"mBio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in the context of a genome-wide screen; FRYL interaction reported as secondary finding, no functional follow-up on FRYL specifically","pmids":["31594818"],"is_preprint":false},{"year":2024,"finding":"Heterozygous de novo loss-of-function variants in FRYL cause a dominant neurodevelopmental disorder with developmental delay, intellectual disability, and dysmorphic features in humans (haploinsufficiency mechanism). Drosophila fry (FRYL ortholog) is expressed in neurons of the central nervous system (not glia), and homozygous fry LoF is lethal. Loss of fry in mutant clones causes wing and compound eye defects. Knockin modeling of four human missense variants showed one behaves as severe LoF, two as partial LoF, and one as neutral, functionally classifying variant pathogenicity.","method":"Human genetics (14 individuals with de novo variants), Drosophila fry knockout and knockin allele modeling, mosaic clone analysis, tissue expression (immunostaining for neuronal localization)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (human genetics, Drosophila LoF, knockin allele modeling, subcellular localization), multiple labs, replicated across 14 individuals","pmids":["38479391"],"is_preprint":false},{"year":2025,"finding":"Homer scaffolding proteins directly interact with FRYL via their EVH1 domains (identified by direct binding experiments). FRYL functions as an NDR kinase scaffold downstream of the Crumbs polarity complex. Functionally, Homers antagonize FRYL to promote YAP activation, while cooperating with FRYL to enhance Wnt/β-catenin signaling—revealing pathway-selective regulation. FRYL promotes formation of spherical, liquid-like Homer condensates in cytoplasm of non-polarized epithelial and colorectal cancer cells, modulating condensate topology and signaling output.","method":"Co-IP/pulldown (EVH1 domain interaction), overexpression/knockdown functional assays for YAP and Wnt signaling readouts, live-cell imaging of condensates, phase separation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus multiple functional readouts (YAP, Wnt, condensate properties); preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.07.23.666266"],"is_preprint":true}],"current_model":"FRYL (AF4p12) is an evolutionarily conserved large scaffold protein that functions as a transcriptional coactivator—acting within NOTCH1 and JAG/NOTCH signaling complexes to regulate target gene expression (including sGC subunits in vascular smooth muscle), interacting with NDR1 kinase (preferentially in its active conformation), and modulating Homer condensate-mediated YAP and Wnt/β-catenin signaling downstream of the Crumbs polarity complex; in vivo, FRYL is required for kidney tubular development in mice and for neuronal development in flies, and heterozygous loss-of-function variants in humans cause a dominant neurodevelopmental disorder via haploinsufficiency."},"narrative":{"mechanistic_narrative":"FRYL is a large evolutionarily conserved scaffold protein that operates as a transcriptional coactivator within developmental signaling complexes and as an organizer of NDR kinase signaling [PMID:28465505, PMID:38479391]. In the nucleus, FRYL associates with the NOTCH1 activation complex alongside the PBAF remodeler and the histone demethylases LSD1 and PHF8 at Notch target genes [PMID:23022380], and acts within JAG/NOTCH signaling together with MAML2 to drive expression of soluble guanylyl cyclase (GUCY1A3/GUCY1B3) in arterial smooth muscle [PMID:28465505]. FRYL was first identified as the COOH-terminal MLL fusion partner AF4p12 in t(4;11) leukemia, a fragment bearing a leucine zipper that confers transcriptional activation [PMID:16061630]. Beyond transcription, FRYL functions as a Furry-family scaffold for NDR kinase, preferentially binding the activated/open conformation of NDR1 [PMID:29983373], and acts downstream of the Crumbs polarity complex where it binds Homer scaffolding proteins via their EVH1 domains and promotes liquid-like Homer condensates that selectively tune YAP and Wnt/β-catenin signaling output [PMID:bio_10.1101_2025.07.23.666266]. In vivo, FRYL is required for kidney tubular development and maintenance in mice [PMID:29409347] and for neuronal development in Drosophila [PMID:38479391], and heterozygous de novo loss-of-function variants cause a dominant neurodevelopmental disorder via haploinsufficiency [PMID:38479391].","teleology":[{"year":2005,"claim":"Established the first functional handle on FRYL by showing its C-terminal fragment, when fused to MLL in leukemia, carries intrinsic transcriptional activation potential—implicating the protein in gene activation.","evidence":"Cloning of the t(4;11) fusion transcript and Gal4-fusion transcriptional activation reporter assays","pmids":["16061630"],"confidence":"Medium","gaps":["Activation domain assayed only as a Gal4 fusion, not in native FRYL context","No endogenous target genes identified","Does not address full-length FRYL function"]},{"year":2012,"claim":"Placed FRYL within a defined nuclear machine by identifying it as a NOTCH1 activation-complex coactivator, linking it to chromatin remodeling and histone demethylation at Notch targets.","evidence":"Immunoaffinity purification of NOTCH1 nuclear partners with mass spectrometry in T-ALL cells","pmids":["23022380"],"confidence":"Medium","gaps":["Interaction defined by co-purification, not direct binding mapping","Specific FRYL contribution to Notch target transcription not isolated","Single cell-type context"]},{"year":2017,"claim":"Demonstrated a concrete physiological transcriptional output for FRYL: JAG/NOTCH-dependent control of soluble guanylyl cyclase expression in vascular smooth muscle, with relevance to hypertension.","evidence":"Gain/loss-of-function in vascular cells with sGC readout and expression analysis in hypertensive animal models","pmids":["28465505"],"confidence":"Medium","gaps":["Direct DNA/promoter occupancy by FRYL not demonstrated","Mechanism of cooperation with MAML2 unresolved","Causal role in hypertension not established"]},{"year":2018,"claim":"Revealed a transcription-factor-complex partnership beyond Notch by isolating FRYL with the Ldb1-Lhx1 LIM-homeodomain complex.","evidence":"Tandem-affinity purification of Lhx1-associated proteins in Xenopus","pmids":["30375416"],"confidence":"Low","gaps":["Single TAP experiment with no functional follow-up for FRYL","Study focused on the FRY paralog","Direct vs indirect association unclear"]},{"year":2018,"claim":"Established an essential developmental requirement for FRYL in mammalian organogenesis, localizing its function to renal tubular development and maintenance.","evidence":"Gene-trap null mouse with histopathology and tissue expression analysis","pmids":["29409347"],"confidence":"Medium","gaps":["Molecular pathway connecting FRYL loss to tubular cell detachment unknown","Cause of perinatal lethality not defined","No link to transcriptional partners in kidney"]},{"year":2018,"claim":"Connected FRYL to NDR kinase signaling as a Furry-family scaffold and defined conformational selectivity, showing it binds the activated/open state of NDR1.","evidence":"Crystal structure of NDR1 kinase domain with activation-segment mutagenesis and co-immunoprecipitation","pmids":["29983373"],"confidence":"Medium","gaps":["FRYL binding inferred from NDR1 deletion-mutant co-IP, not direct interface mapping","Functional consequence of FRYL-NDR1 binding not tested","No cellular context for the interaction"]},{"year":2019,"claim":"Identified FRYL as a physical associate of NHLRC2 in macrophages, expanding its interaction landscape.","evidence":"Immunoprecipitation of NHLRC2 in macrophages","pmids":["31594818"],"confidence":"Low","gaps":["Single Co-IP as a secondary finding with no reciprocal validation","No functional consequence assessed for FRYL","Direct vs complex-mediated interaction unresolved"]},{"year":2021,"claim":"Defined FRYL as a direct miR-1205 target overexpressed in prostate cancer, while excluding its role in miR-1205-driven neuroendocrine differentiation.","evidence":"miRNA target validation and FRYL knockdown in an NED induction assay in prostate cancer cells","pmids":["34386489"],"confidence":"Medium","gaps":["Functional role of FRYL overexpression in prostate cancer not established","Negative NED result does not exclude other oncogenic functions","Mechanism of FRYL overexpression beyond miR-1205 unknown"]},{"year":2024,"claim":"Established FRYL as a haploinsufficient disease gene by linking heterozygous de novo loss-of-function variants to a dominant neurodevelopmental disorder and functionally classifying variant pathogenicity in an in vivo model.","evidence":"Human genetics in 14 individuals plus Drosophila fry knockout, knockin variant modeling, mosaic clone analysis, and neuronal expression","pmids":["38479391"],"confidence":"High","gaps":["Molecular pathway through which FRYL loss disrupts neurodevelopment not defined","Which signaling partner (NDR, Notch, Homer) mediates the phenotype unknown","Genotype-phenotype correlation across the variant spectrum incomplete"]},{"year":2025,"claim":"Integrated FRYL into polarity-driven signaling by showing it scaffolds NDR kinase downstream of Crumbs, binds Homer EVH1 domains, and drives liquid-like Homer condensates that selectively partition YAP versus Wnt/β-catenin output.","evidence":"EVH1-domain pulldowns, YAP/Wnt functional assays, and live-cell imaging of phase-separated condensates (preprint)","pmids":["bio_10.1101_2025.07.23.666266"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct demonstration of FRYL in the Crumbs complex limited","Quantitative contribution of condensate topology to signaling not fully resolved"]},{"year":null,"claim":"It remains unknown how FRYL's distinct molecular roles—nuclear transcriptional coactivation, NDR kinase scaffolding, and Homer condensate organization—are integrated to produce its developmental and disease phenotypes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism connecting transcriptional and cytoplasmic scaffolding functions","Tissue-specific partner usage undefined","No structural model of full-length FRYL or its scaffolding interfaces"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2]}],"complexes":["NOTCH1 nuclear activation complex"],"partners":["NOTCH1","MAML2","NDR1","HOMER","LDB1","LHX1","NHLRC2","MLL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94915","full_name":"Protein furry homolog-like","aliases":["ALL1-fused gene from chromosome 4p12 protein"],"length_aa":3013,"mass_kda":339.6,"function":"Plays a key role in maintaining the integrity of polarized cell extensions during morphogenesis, regulates the actin cytoskeleton and plays a key role in patterning sensory neuron dendritic fields by promoting avoidance between homologous dendrites as well as by limiting dendritic branching (By similarity). May function as a transcriptional activator","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O94915/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRYL","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HOMER1","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FRYL","total_profiled":1310},"omim":[{"mim_id":"621067","title":"NEURODEVELOPMENTAL DISORDER WITH POOR GROWTH, ABSENT SPEECH, PROGRESSIVE ATAXIA, AND DYSMORPHIC FACIES; NEDGSAF","url":"https://www.omim.org/entry/621067"},{"mim_id":"621049","title":"PAN-CHUNG-BELLEN SYNDROME; PCBS","url":"https://www.omim.org/entry/621049"},{"mim_id":"620798","title":"FRY-LIKE TRANSCRIPTION COACTIVATOR; FRYL","url":"https://www.omim.org/entry/620798"},{"mim_id":"614818","title":"FRY MICROTUBULE-BINDING PROTEIN; FRY","url":"https://www.omim.org/entry/614818"},{"mim_id":"606964","title":"SERINE/THREONINE PROTEIN KINASE 38; STK38","url":"https://www.omim.org/entry/606964"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FRYL"},"hgnc":{"alias_symbol":["DKFZp686E205","AF4p12","MOR2"],"prev_symbol":["KIAA0826"]},"alphafold":{"accession":"O94915","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94915","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94915-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94915-2-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRYL","jax_strain_url":"https://www.jax.org/strain/search?query=FRYL"},"sequence":{"accession":"O94915","fasta_url":"https://rest.uniprot.org/uniprotkb/O94915.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94915/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94915"}},"corpus_meta":[{"pmid":"23022380","id":"PMC_23022380","title":"NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic 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trophoblasts.","date":"2023","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/37331027","citation_count":0,"is_preprint":false},{"pmid":"42220229","id":"PMC_42220229","title":"Real-world-data for phenotypes and genotypes of rare monogenic genetic epilepsies and genes of uncertain significance for epilepsy.","date":"2026","source":"Epilepsia open","url":"https://pubmed.ncbi.nlm.nih.gov/42220229","citation_count":0,"is_preprint":false},{"pmid":"41674076","id":"PMC_41674076","title":"Patient-informed CRISPR screen identifies FLNB as a congenital heart disease and ciliopathy gene.","date":"2026","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/41674076","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.23.666266","title":"Homer condensates orchestrate YAP-Wnt signaling crosstalk downstream of the Crumbs polarity complex","date":"2025-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.23.666266","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19940,"output_tokens":2667,"usd":0.049912,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9944,"output_tokens":3545,"usd":0.069172,"stage2_stop_reason":"end_turn"},"total_usd":0.119084,"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\": 2005,\n      \"finding\": \"AF4p12 (FRYL) was identified as a novel MLL fusion partner resulting from t(4;11)(p12;q23) translocation in leukemia. The COOH-terminal part of AF4p12 fused to MLL contains a leucine zipper motif and exhibits transcriptional activation properties when fused to Gal4 DNA-binding domains in transient transfection assays, suggesting the AF4p12 fragment contributes to oncogenic activation of MLL.\",\n      \"method\": \"Cloning of fusion transcript, domain analysis, transient transfection transcriptional activation assay with Gal4 fusion constructs\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (transcriptional activation) with domain identification, single lab, two orthogonal methods (fusion cloning + Gal4 reporter)\",\n      \"pmids\": [\"16061630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FRYL (AF4p12) was identified as a component of the NOTCH1 nuclear activation complex in T-ALL cells, where it functions as a transcription coactivator alongside the PBAF nucleosome remodeling complex and histone demethylases LSD1 and PHF8 at Notch-target genes.\",\n      \"method\": \"Immunoaffinity purification of NOTCH1 nuclear partners from T-ALL cells (mass spectrometry-based interactome)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunoaffinity purification/MS identifying FRYL as a NOTCH1 partner, large interactome study but specifically validated the complex composition; single lab\",\n      \"pmids\": [\"23022380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FRYL functions as a coactivator in the JAG/NOTCH signaling pathway to control expression of soluble guanylyl cyclase (sGC, encoded by GUCY1A3/GUCY1B3) in arterial smooth muscle cells. Gain- and loss-of-function experiments demonstrated that JAG/NOTCH signaling controls sGC expression together with MAML2 and FRYL, and FRYL expression was reduced in hypertension models.\",\n      \"method\": \"Gain- and loss-of-function experiments (overexpression and knockdown) in vascular cells, Western blotting, analysis of transcription factor binding motifs, gene expression analysis in angiotensin II-treated mice and hypertensive rats\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain/loss-of-function experiments with defined molecular readout (sGC expression), single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"28465505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FRYL (Fryl) was isolated as a binding partner of the Ldb1-Lhx1 transcription factor complex by tandem-affinity purification in Xenopus, indicating FRYL can associate with this LIM-homeodomain transcriptional complex.\",\n      \"method\": \"Tandem-affinity purification of Lhx1-associated proteins\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/TAP experiment identifying interaction, single lab, no functional follow-up specifically for FRYL (study focused on FRY paralog)\",\n      \"pmids\": [\"30375416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Fryl knockout mice (null mutation by gene trapping) die soon after birth; rare survivors develop hydronephrosis and die before age 1. Fryl is expressed in renal tubular tissues (glomeruli, convoluted and collecting tubules), and Fryl-/- neonates show abnormal lining cell detachments in collecting and convoluted tubules, establishing a required role for Fryl in kidney tubular development and maintenance.\",\n      \"method\": \"Gene-trap null mouse generation, histopathological analysis, tissue expression analysis (RT-PCR/immunostaining)\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined morphological phenotype and tissue expression localization, single lab, two orthogonal methods (histology + expression)\",\n      \"pmids\": [\"29409347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of the auto-inhibitory activation segment of human NDR1 kinase causes a marked increase in association with the Furry scaffold (FRYL), indicating FRYL preferentially interacts with an activated/open conformation of NDR1.\",\n      \"method\": \"Crystal structure of NDR1 kinase domain; mutagenesis of activation segment; co-immunoprecipitation to assess Furry scaffold interaction\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — crystal structure plus mutagenesis plus binding assay in single study; interaction with FRYL based on co-IP of deletion mutant, single lab\",\n      \"pmids\": [\"29983373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-1205 directly targets FRYL, as demonstrated by identification and validation of FRYL as a direct molecular target of miR-1205 in prostate cancer cells. FRYL is overexpressed in prostate cancer cells and tissues. However, FRYL knockdown did not reduce neuroendocrine differentiation (NED), showing that miR-1205 induces NED independently of FRYL.\",\n      \"method\": \"miRNA target prediction and validation (luciferase reporter assay implied), FRYL knockdown in NED induction assay, expression analysis in cell lines and tissues\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation with knockdown and defined readout; negative result for NED is also experimentally established; single lab\",\n      \"pmids\": [\"34386489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FRYL was identified as a binding partner of NHLRC2 by immunoprecipitation in macrophages, along with EIF2AK2 and KLHL13.\",\n      \"method\": \"Immunoprecipitation of NHLRC2 followed by identification of FRYL as interacting protein\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in the context of a genome-wide screen; FRYL interaction reported as secondary finding, no functional follow-up on FRYL specifically\",\n      \"pmids\": [\"31594818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Heterozygous de novo loss-of-function variants in FRYL cause a dominant neurodevelopmental disorder with developmental delay, intellectual disability, and dysmorphic features in humans (haploinsufficiency mechanism). Drosophila fry (FRYL ortholog) is expressed in neurons of the central nervous system (not glia), and homozygous fry LoF is lethal. Loss of fry in mutant clones causes wing and compound eye defects. Knockin modeling of four human missense variants showed one behaves as severe LoF, two as partial LoF, and one as neutral, functionally classifying variant pathogenicity.\",\n      \"method\": \"Human genetics (14 individuals with de novo variants), Drosophila fry knockout and knockin allele modeling, mosaic clone analysis, tissue expression (immunostaining for neuronal localization)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (human genetics, Drosophila LoF, knockin allele modeling, subcellular localization), multiple labs, replicated across 14 individuals\",\n      \"pmids\": [\"38479391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homer scaffolding proteins directly interact with FRYL via their EVH1 domains (identified by direct binding experiments). FRYL functions as an NDR kinase scaffold downstream of the Crumbs polarity complex. Functionally, Homers antagonize FRYL to promote YAP activation, while cooperating with FRYL to enhance Wnt/β-catenin signaling—revealing pathway-selective regulation. FRYL promotes formation of spherical, liquid-like Homer condensates in cytoplasm of non-polarized epithelial and colorectal cancer cells, modulating condensate topology and signaling output.\",\n      \"method\": \"Co-IP/pulldown (EVH1 domain interaction), overexpression/knockdown functional assays for YAP and Wnt signaling readouts, live-cell imaging of condensates, phase separation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus multiple functional readouts (YAP, Wnt, condensate properties); preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.23.666266\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"FRYL (AF4p12) is an evolutionarily conserved large scaffold protein that functions as a transcriptional coactivator—acting within NOTCH1 and JAG/NOTCH signaling complexes to regulate target gene expression (including sGC subunits in vascular smooth muscle), interacting with NDR1 kinase (preferentially in its active conformation), and modulating Homer condensate-mediated YAP and Wnt/β-catenin signaling downstream of the Crumbs polarity complex; in vivo, FRYL is required for kidney tubular development in mice and for neuronal development in flies, and heterozygous loss-of-function variants in humans cause a dominant neurodevelopmental disorder via haploinsufficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRYL is a large evolutionarily conserved scaffold protein that operates as a transcriptional coactivator within developmental signaling complexes and as an organizer of NDR kinase signaling [#2, #8]. In the nucleus, FRYL associates with the NOTCH1 activation complex alongside the PBAF remodeler and the histone demethylases LSD1 and PHF8 at Notch target genes [#1], and acts within JAG/NOTCH signaling together with MAML2 to drive expression of soluble guanylyl cyclase (GUCY1A3/GUCY1B3) in arterial smooth muscle [#2]. FRYL was first identified as the COOH-terminal MLL fusion partner AF4p12 in t(4;11) leukemia, a fragment bearing a leucine zipper that confers transcriptional activation [#0]. Beyond transcription, FRYL functions as a Furry-family scaffold for NDR kinase, preferentially binding the activated/open conformation of NDR1 [#5], and acts downstream of the Crumbs polarity complex where it binds Homer scaffolding proteins via their EVH1 domains and promotes liquid-like Homer condensates that selectively tune YAP and Wnt/\\u03b2-catenin signaling output [#9]. In vivo, FRYL is required for kidney tubular development and maintenance in mice [#4] and for neuronal development in Drosophila [#8], and heterozygous de novo loss-of-function variants cause a dominant neurodevelopmental disorder via haploinsufficiency [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the first functional handle on FRYL by showing its C-terminal fragment, when fused to MLL in leukemia, carries intrinsic transcriptional activation potential\\u2014implicating the protein in gene activation.\",\n      \"evidence\": \"Cloning of the t(4;11) fusion transcript and Gal4-fusion transcriptional activation reporter assays\",\n      \"pmids\": [\"16061630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activation domain assayed only as a Gal4 fusion, not in native FRYL context\", \"No endogenous target genes identified\", \"Does not address full-length FRYL function\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed FRYL within a defined nuclear machine by identifying it as a NOTCH1 activation-complex coactivator, linking it to chromatin remodeling and histone demethylation at Notch targets.\",\n      \"evidence\": \"Immunoaffinity purification of NOTCH1 nuclear partners with mass spectrometry in T-ALL cells\",\n      \"pmids\": [\"23022380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction defined by co-purification, not direct binding mapping\", \"Specific FRYL contribution to Notch target transcription not isolated\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a concrete physiological transcriptional output for FRYL: JAG/NOTCH-dependent control of soluble guanylyl cyclase expression in vascular smooth muscle, with relevance to hypertension.\",\n      \"evidence\": \"Gain/loss-of-function in vascular cells with sGC readout and expression analysis in hypertensive animal models\",\n      \"pmids\": [\"28465505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA/promoter occupancy by FRYL not demonstrated\", \"Mechanism of cooperation with MAML2 unresolved\", \"Causal role in hypertension not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a transcription-factor-complex partnership beyond Notch by isolating FRYL with the Ldb1-Lhx1 LIM-homeodomain complex.\",\n      \"evidence\": \"Tandem-affinity purification of Lhx1-associated proteins in Xenopus\",\n      \"pmids\": [\"30375416\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single TAP experiment with no functional follow-up for FRYL\", \"Study focused on the FRY paralog\", \"Direct vs indirect association unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established an essential developmental requirement for FRYL in mammalian organogenesis, localizing its function to renal tubular development and maintenance.\",\n      \"evidence\": \"Gene-trap null mouse with histopathology and tissue expression analysis\",\n      \"pmids\": [\"29409347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway connecting FRYL loss to tubular cell detachment unknown\", \"Cause of perinatal lethality not defined\", \"No link to transcriptional partners in kidney\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected FRYL to NDR kinase signaling as a Furry-family scaffold and defined conformational selectivity, showing it binds the activated/open state of NDR1.\",\n      \"evidence\": \"Crystal structure of NDR1 kinase domain with activation-segment mutagenesis and co-immunoprecipitation\",\n      \"pmids\": [\"29983373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FRYL binding inferred from NDR1 deletion-mutant co-IP, not direct interface mapping\", \"Functional consequence of FRYL-NDR1 binding not tested\", \"No cellular context for the interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified FRYL as a physical associate of NHLRC2 in macrophages, expanding its interaction landscape.\",\n      \"evidence\": \"Immunoprecipitation of NHLRC2 in macrophages\",\n      \"pmids\": [\"31594818\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP as a secondary finding with no reciprocal validation\", \"No functional consequence assessed for FRYL\", \"Direct vs complex-mediated interaction unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined FRYL as a direct miR-1205 target overexpressed in prostate cancer, while excluding its role in miR-1205-driven neuroendocrine differentiation.\",\n      \"evidence\": \"miRNA target validation and FRYL knockdown in an NED induction assay in prostate cancer cells\",\n      \"pmids\": [\"34386489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of FRYL overexpression in prostate cancer not established\", \"Negative NED result does not exclude other oncogenic functions\", \"Mechanism of FRYL overexpression beyond miR-1205 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established FRYL as a haploinsufficient disease gene by linking heterozygous de novo loss-of-function variants to a dominant neurodevelopmental disorder and functionally classifying variant pathogenicity in an in vivo model.\",\n      \"evidence\": \"Human genetics in 14 individuals plus Drosophila fry knockout, knockin variant modeling, mosaic clone analysis, and neuronal expression\",\n      \"pmids\": [\"38479391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway through which FRYL loss disrupts neurodevelopment not defined\", \"Which signaling partner (NDR, Notch, Homer) mediates the phenotype unknown\", \"Genotype-phenotype correlation across the variant spectrum incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated FRYL into polarity-driven signaling by showing it scaffolds NDR kinase downstream of Crumbs, binds Homer EVH1 domains, and drives liquid-like Homer condensates that selectively partition YAP versus Wnt/\\u03b2-catenin output.\",\n      \"evidence\": \"EVH1-domain pulldowns, YAP/Wnt functional assays, and live-cell imaging of phase-separated condensates (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.23.666266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct demonstration of FRYL in the Crumbs complex limited\", \"Quantitative contribution of condensate topology to signaling not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FRYL's distinct molecular roles\\u2014nuclear transcriptional coactivation, NDR kinase scaffolding, and Homer condensate organization\\u2014are integrated to produce its developmental and disease phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism connecting transcriptional and cytoplasmic scaffolding functions\", \"Tissue-specific partner usage undefined\", \"No structural model of full-length FRYL or its scaffolding interfaces\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"NOTCH1 nuclear activation complex\"],\n    \"partners\": [\"NOTCH1\", \"MAML2\", \"NDR1\", \"HOMER\", \"LDB1\", \"LHX1\", \"NHLRC2\", \"MLL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}