{"gene":"FRY","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2010,"finding":"Drosophila Fry protein physically interacts with the NDR kinase Tricornered (Trc): co-immunoprecipitation from wing discs demonstrated the interaction. Full-length Fry and Trc show only partial co-localization in growing bristles, while an N-terminal fragment of Fry shows near-complete co-localization with Trc, indicating the interaction is transient and regulated. Fry accumulates at the distal tip of growing bristles and is highly mobile in both bristles and dendrites, suggesting a role in directing intracellular transport for polarized growth.","method":"Co-immunoprecipitation from wing discs; in vivo live imaging of GFP-tagged Fry; N- and C-terminal tagging with functional rescue of fry null lethality; transgenic complementation","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, live imaging with GFP-tagged protein, null-rescue transgene, multiple orthogonal methods in single focused study on this protein","pmids":["20406475"],"is_preprint":false},{"year":2010,"finding":"In Drosophila wing cells prior to terminal differentiation, Fry (together with its binding partner Trc, an NDR kinase) regulates cell shape, F-actin levels, timing of differentiation, and expression of DE-Cadherin and multiple wing hairs (mwh). Loss-of-function of trc/fry causes changes in cellular F-actin levels and altered cell shape. Fry regulates DE-cadherin and mwh expression via a pathway distinct from the Warts/Yorkie tumor suppressor axis.","method":"Drosophila loss-of-function genetics (trc and fry mutants); phalloidin staining for F-actin; immunostaining for DE-Cadherin and Mwh; genetic epistasis with yorkie","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotypes and epistasis, single lab, multiple readouts","pmids":["20211163"],"is_preprint":false},{"year":2013,"finding":"The rat ortholog Fry was identified as a candidate mammary carcinoma susceptibility (Mcs) gene. Full-length Fry mRNA (~13 kbp) was cloned and sequenced. Comparison between resistant (Copenhagen) and susceptible (Fischer 344) rat strains identified two non-synonymous SNPs, one of which creates a putative de novo phosphorylation site. Fry expression is reduced in a majority of rat mammary tumors, and FRY activity appears reduced in human breast carcinoma cell lines.","method":"Genetic linkage/backcross mapping (LOD ~8.6); cDNA cloning and sequencing; SNP analysis between strains; RT-PCR/expression analysis in tumors; sequence analysis of human breast carcinoma lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic mapping with expression analysis, single lab, multiple methods but no functional reconstitution of the SNP effect","pmids":["24023717"],"is_preprint":false},{"year":2019,"finding":"Conditional knockout of Fry in mouse mammary glands (using Cre-loxP) demonstrated that Fry is required for normal mammary gland development during pregnancy but is dispensable in virgin mammary glands. Loss of Fry led to more lateral buds and smaller, undistended lobuloalveoli during late pregnancy. Ectopic expression of FRY in breast cancer cell lines (MDA-MB-231 and BT474) suppressed growth and proliferation and altered cell morphology. Transcriptomic analysis indicated FRY activates the Hippo/YAP pathway and interacts with protein kinase-relevant signaling pathways.","method":"Conditional knockout mouse (Cre-loxP); mammary gland histology; ectopic FRY overexpression in breast cancer cell lines with growth/proliferation assays; genome-wide transcriptomic analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined morphological phenotype, in vitro overexpression with functional readout, transcriptomics; single lab, multiple orthogonal methods","pmids":["31824855"],"is_preprint":false}],"current_model":"FRY encodes a large, evolutionarily conserved scaffold protein that physically interacts with NDR family kinases (Tricornered/Trc in Drosophila) to regulate polarized cell growth, actin cytoskeleton organization, and cell shape; in mammals, FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation, at least in part through activation of the Hippo/YAP signaling pathway."},"narrative":{"mechanistic_narrative":"FRY encodes a large, conserved scaffold protein that partners with NDR family kinases to control polarized cell growth, actin organization, and cell shape [PMID:20406475, PMID:20211163]. In Drosophila, Fry physically associates with the NDR kinase Tricornered (Trc) through a transient, regulated interaction; Fry is highly mobile and accumulates at the distal tip of growing bristles, consistent with a role in directing intracellular transport for polarized growth [PMID:20406475]. Together with Trc, Fry governs cell shape, cellular F-actin levels, the timing of differentiation, and expression of DE-Cadherin and multiple wing hairs (mwh) in pre-differentiation wing cells, acting through a route distinct from the Warts/Yorkie axis [PMID:20211163]. In mammals, FRY is required for mammary lobuloalveolar development during pregnancy but is dispensable in virgin glands, and ectopic FRY suppresses breast cancer cell growth and proliferation while altering morphology, an activity linked to activation of Hippo/YAP signaling [PMID:31824855]. Consistent with a tumor-suppressive role, the rat Fry ortholog maps as a mammary carcinoma susceptibility gene and is downregulated in mammary tumors [PMID:24023717].","teleology":[{"year":2010,"claim":"Establishing whether Fry works with NDR kinases physically, this work showed Fry directly partners with Tricornered and localizes dynamically to sites of polarized growth, defining Fry as a regulated scaffold for NDR-kinase-dependent morphogenesis.","evidence":"Co-immunoprecipitation from wing discs plus in vivo live imaging of GFP-tagged Fry and null-rescue transgenes in Drosophila","pmids":["20406475"],"confidence":"High","gaps":["Molecular basis of the transient Fry-Trc interaction not resolved","Cargo or transport machinery directed by Fry not identified","No structural characterization of the Fry-Trc complex"]},{"year":2010,"claim":"To define what cellular processes Fry controls, loss-of-function genetics placed Fry/Trc upstream of F-actin levels, cell shape, differentiation timing, and DE-Cadherin/mwh expression, and distinguished this from the Warts/Yorkie tumor suppressor pathway.","evidence":"Drosophila trc/fry loss-of-function mutants with phalloidin and immunostaining readouts and yorkie epistasis","pmids":["20211163"],"confidence":"Medium","gaps":["Mechanism linking Fry to DE-Cadherin/mwh transcription unknown","Direct effectors downstream of the Fry/Trc module not identified"]},{"year":2013,"claim":"Asking whether FRY has a disease-relevant role, genetic mapping in rats identified Fry as a mammary carcinoma susceptibility candidate that is downregulated in tumors, implicating FRY as a tumor suppressor.","evidence":"Linkage/backcross mapping (LOD ~8.6), cDNA cloning, SNP analysis between rat strains, and expression analysis in tumors and human breast carcinoma lines","pmids":["24023717"],"confidence":"Medium","gaps":["Functional effect of the candidate SNPs not reconstituted","Causality of FRY loss in tumorigenesis not directly tested in this study"]},{"year":2019,"claim":"To test FRY function in mammalian tissue, conditional knockout and overexpression showed FRY is required for pregnancy-associated lobuloalveolar development and suppresses breast cancer cell proliferation via Hippo/YAP activation, connecting the conserved scaffold to mammalian morphogenesis and growth control.","evidence":"Cre-loxP conditional knockout mouse with mammary histology, ectopic FRY expression in MDA-MB-231 and BT474 cells with proliferation assays, and genome-wide transcriptomics","pmids":["31824855"],"confidence":"Medium","gaps":["Direct molecular link between FRY and Hippo/YAP components not defined","Whether mammalian FRY acts through an NDR kinase as in Drosophila not established here","Mechanism of the lobuloalveolar defect unresolved"]},{"year":null,"claim":"How FRY mechanistically activates Hippo/YAP signaling and whether its mammalian functions depend on the NDR-kinase partnership established in Drosophila remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified direct biochemical link between mammalian FRY and Hippo/YAP components","NDR kinase partner for mammalian FRY not characterized in the corpus","No structural or domain-level mechanism for FRY scaffold function"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3]}],"complexes":[],"partners":["TRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5TBA9","full_name":"Protein furry homolog","aliases":[],"length_aa":3013,"mass_kda":338.9,"function":"Plays a crucial role in the structural integrity of mitotic centrosomes and in the maintenance of spindle bipolarity by promoting PLK1 activity at the spindle poles in early mitosis. May function as a scaffold promoting the interaction between AURKA and PLK1, thereby enhancing AURKA-mediated PLK1 phosphorylation","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q5TBA9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRY","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FRY","total_profiled":1310},"omim":[{"mim_id":"621565","title":"YU-KURY NEURODEVELOPMENTAL SYNDROME; YKNS","url":"https://www.omim.org/entry/621565"},{"mim_id":"621074","title":"MITOTIC DEACETYLASE-ASSOCIATED SANT DOMAIN PROTEIN; MIDEAS","url":"https://www.omim.org/entry/621074"},{"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":"619769","title":"MACROCEPHALY, NEURODEVELOPMENTAL DELAY, LYMPHOID HYPERPLASIA, AND PERSISTENT FETAL HEMOGLOBIN; MNDLFH","url":"https://www.omim.org/entry/619769"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FRY"},"hgnc":{"alias_symbol":["bA37E23.1","13CDNA73","CG003"],"prev_symbol":["C13orf14"]},"alphafold":{"accession":"Q5TBA9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TBA9","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRY","jax_strain_url":"https://www.jax.org/strain/search?query=FRY"},"sequence":{"accession":"Q5TBA9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5TBA9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5TBA9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TBA9"}},"corpus_meta":[{"pmid":"11555854","id":"PMC_11555854","title":"Developmental expression of cytochrome P450 aromatase genes (CYP19a and CYP19b) in zebrafish fry (Danio rerio).","date":"2001","source":"The Journal of experimental 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biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/17693713","citation_count":13,"is_preprint":false},{"pmid":"31824855","id":"PMC_31824855","title":"Fry Is Required for Mammary Gland Development During Pregnant Periods and Affects the Morphology and Growth of Breast Cancer Cells.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31824855","citation_count":12,"is_preprint":false},{"pmid":"37178986","id":"PMC_37178986","title":"Immunological response of 35 and 42 days old Asian seabass (Lates calcarifer, Bloch 1790) fry following immersion immunization with Streptococcus iniae heat-killed vaccine.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37178986","citation_count":12,"is_preprint":false},{"pmid":"24023717","id":"PMC_24023717","title":"Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs 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Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/12297368","citation_count":10,"is_preprint":false},{"pmid":"35000111","id":"PMC_35000111","title":"The Combined Effects of Propionic Acid and a Mixture of Bacillus spp. Probiotic in a Plant Protein-Rich Diet on Growth, Digestive Enzyme Activities, Antioxidant Capacity, and Immune-Related Genes mRNA Transcript Abundance in Lates calcarifer Fry.","date":"2022","source":"Probiotics and antimicrobial proteins","url":"https://pubmed.ncbi.nlm.nih.gov/35000111","citation_count":9,"is_preprint":false},{"pmid":"30191410","id":"PMC_30191410","title":"Growth Behavior and Fatty Acid Production of Probiotics, Pediococcus acidilactici and Lactococcus lactis, at Different Concentrations of Fructooligosaccharide: Studies Validating Clinical Efficacy of Selected Synbiotics on Growth Performance of Caspian Roach (Rutilus frisii kutum) Fry.","date":"2019","source":"Probiotics and antimicrobial proteins","url":"https://pubmed.ncbi.nlm.nih.gov/30191410","citation_count":9,"is_preprint":false},{"pmid":"31838613","id":"PMC_31838613","title":"Efficacy of dietary exogenous enzyme supplementation on growth performance, antioxidant activity, and digestive enzymes of common carp (Cyprinus carpio) fry.","date":"2019","source":"Fish physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31838613","citation_count":9,"is_preprint":false},{"pmid":"35940539","id":"PMC_35940539","title":"Methionine played a positive role in improving the intestinal digestion capacity, anti-inflammatory reaction and oxidation resistance of grass carp, Ctenopharyngodon idella, fry.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35940539","citation_count":9,"is_preprint":false},{"pmid":"26379055","id":"PMC_26379055","title":"Meta-Analysis of Microarray Data of Rainbow Trout Fry Gonad Differentiation Modulated by Ethynylestradiol.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26379055","citation_count":9,"is_preprint":false},{"pmid":"7522310","id":"PMC_7522310","title":"Cranial nerves and brain fiber systems of the medaka fry as observed by a whole-mount staining method.","date":"1994","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/7522310","citation_count":9,"is_preprint":false},{"pmid":"28112058","id":"PMC_28112058","title":"A n-3 PUFA depletion applied to rainbow trout fry (Oncorhynchus mykiss) does not modulate its subsequent lipid bioconversion capacity.","date":"2017","source":"The British journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/28112058","citation_count":9,"is_preprint":false},{"pmid":"24233119","id":"PMC_24233119","title":"Accumulation of waterborne selenium by rainbow trout (Salmo gairdneri), eggs, fry and juveniles.","date":"1986","source":"Fish physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24233119","citation_count":9,"is_preprint":false},{"pmid":"29654925","id":"PMC_29654925","title":"Effects of bisphenol A (BPA) on brain-specific expression of cyp19a1b gene in swim-up fry of Labeo rohita.","date":"2018","source":"Comparative biochemistry and physiology. Toxicology & pharmacology : CBP","url":"https://pubmed.ncbi.nlm.nih.gov/29654925","citation_count":8,"is_preprint":false},{"pmid":"10556371","id":"PMC_10556371","title":"Biochemical responses of fish sac fry and a primary cell culture of fish hepatocytes exposed to polychlorinated naphthalenes.","date":"2000","source":"Archives of environmental contamination and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/10556371","citation_count":8,"is_preprint":false},{"pmid":"34202225","id":"PMC_34202225","title":"Modulation of Energy Metabolism and Epigenetic Landscape in Rainbow Trout Fry by a Parental Low Protein/High Carbohydrate Diet.","date":"2021","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34202225","citation_count":8,"is_preprint":false},{"pmid":"29661132","id":"PMC_29661132","title":"Transcriptional development of phospholipid and lipoprotein metabolism in different intestinal regions of Atlantic salmon (Salmo salar) fry.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29661132","citation_count":8,"is_preprint":false},{"pmid":"31950318","id":"PMC_31950318","title":"Effects of dietary myo-inositol on growth, antioxidative capacity, and nonspecific immunity in skin mucus of taimen Hucho taimen fry.","date":"2020","source":"Fish physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31950318","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52159,"output_tokens":1650,"usd":0.090613,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7998,"output_tokens":2016,"usd":0.045195,"stage2_stop_reason":"end_turn"},"total_usd":0.135808,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the human/mammalian gene FRY (also known as furry, C13orf14, etc.) — a large conserved protein that functions as a scaffold for NDR kinases.\n\nThe vast majority of papers are about fish fry (juvenile fish), aquaculture, virology, or completely unrelated topics. I need to filter for papers about the FRY gene/protein.\n\nRelevant papers:\n- **[50]** \"The Drosophila Fry protein interacts with Trc and is highly mobile in vivo\" — directly about the Fry/furry protein (Drosophila ortholog)\n- **[25]** \"Regulation of cell shape, wing hair initiation and the actin cytoskeleton by Trc/Fry and Wts/Mats complexes\" — directly about Drosophila Fry\n- **[75]** \"Fry Is Required for Mammary Gland Development During Pregnant Periods and Affects the Morphology and Growth of Breast Cancer Cells\" — mammalian FRY\n- **[77]** \"Mapping of Mcs30...identification of fry as a candidate Mcs gene\" — rat/mammalian Fry\n\nAll other papers are about fish fry (juvenile fish) or unrelated topics.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Fry protein physically interacts with the NDR kinase Tricornered (Trc): co-immunoprecipitation from wing discs demonstrated the interaction. Full-length Fry and Trc show only partial co-localization in growing bristles, while an N-terminal fragment of Fry shows near-complete co-localization with Trc, indicating the interaction is transient and regulated. Fry accumulates at the distal tip of growing bristles and is highly mobile in both bristles and dendrites, suggesting a role in directing intracellular transport for polarized growth.\",\n      \"method\": \"Co-immunoprecipitation from wing discs; in vivo live imaging of GFP-tagged Fry; N- and C-terminal tagging with functional rescue of fry null lethality; transgenic complementation\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, live imaging with GFP-tagged protein, null-rescue transgene, multiple orthogonal methods in single focused study on this protein\",\n      \"pmids\": [\"20406475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila wing cells prior to terminal differentiation, Fry (together with its binding partner Trc, an NDR kinase) regulates cell shape, F-actin levels, timing of differentiation, and expression of DE-Cadherin and multiple wing hairs (mwh). Loss-of-function of trc/fry causes changes in cellular F-actin levels and altered cell shape. Fry regulates DE-cadherin and mwh expression via a pathway distinct from the Warts/Yorkie tumor suppressor axis.\",\n      \"method\": \"Drosophila loss-of-function genetics (trc and fry mutants); phalloidin staining for F-actin; immunostaining for DE-Cadherin and Mwh; genetic epistasis with yorkie\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotypes and epistasis, single lab, multiple readouts\",\n      \"pmids\": [\"20211163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The rat ortholog Fry was identified as a candidate mammary carcinoma susceptibility (Mcs) gene. Full-length Fry mRNA (~13 kbp) was cloned and sequenced. Comparison between resistant (Copenhagen) and susceptible (Fischer 344) rat strains identified two non-synonymous SNPs, one of which creates a putative de novo phosphorylation site. Fry expression is reduced in a majority of rat mammary tumors, and FRY activity appears reduced in human breast carcinoma cell lines.\",\n      \"method\": \"Genetic linkage/backcross mapping (LOD ~8.6); cDNA cloning and sequencing; SNP analysis between strains; RT-PCR/expression analysis in tumors; sequence analysis of human breast carcinoma lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic mapping with expression analysis, single lab, multiple methods but no functional reconstitution of the SNP effect\",\n      \"pmids\": [\"24023717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional knockout of Fry in mouse mammary glands (using Cre-loxP) demonstrated that Fry is required for normal mammary gland development during pregnancy but is dispensable in virgin mammary glands. Loss of Fry led to more lateral buds and smaller, undistended lobuloalveoli during late pregnancy. Ectopic expression of FRY in breast cancer cell lines (MDA-MB-231 and BT474) suppressed growth and proliferation and altered cell morphology. Transcriptomic analysis indicated FRY activates the Hippo/YAP pathway and interacts with protein kinase-relevant signaling pathways.\",\n      \"method\": \"Conditional knockout mouse (Cre-loxP); mammary gland histology; ectopic FRY overexpression in breast cancer cell lines with growth/proliferation assays; genome-wide transcriptomic analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined morphological phenotype, in vitro overexpression with functional readout, transcriptomics; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31824855\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRY encodes a large, evolutionarily conserved scaffold protein that physically interacts with NDR family kinases (Tricornered/Trc in Drosophila) to regulate polarized cell growth, actin cytoskeleton organization, and cell shape; in mammals, FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation, at least in part through activation of the Hippo/YAP signaling pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRY encodes a large, conserved scaffold protein that partners with NDR family kinases to control polarized cell growth, actin organization, and cell shape [#0, #1]. In Drosophila, Fry physically associates with the NDR kinase Tricornered (Trc) through a transient, regulated interaction; Fry is highly mobile and accumulates at the distal tip of growing bristles, consistent with a role in directing intracellular transport for polarized growth [#0]. Together with Trc, Fry governs cell shape, cellular F-actin levels, the timing of differentiation, and expression of DE-Cadherin and multiple wing hairs (mwh) in pre-differentiation wing cells, acting through a route distinct from the Warts/Yorkie axis [#1]. In mammals, FRY is required for mammary lobuloalveolar development during pregnancy but is dispensable in virgin glands, and ectopic FRY suppresses breast cancer cell growth and proliferation while altering morphology, an activity linked to activation of Hippo/YAP signaling [#3]. Consistent with a tumor-suppressive role, the rat Fry ortholog maps as a mammary carcinoma susceptibility gene and is downregulated in mammary tumors [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing whether Fry works with NDR kinases physically, this work showed Fry directly partners with Tricornered and localizes dynamically to sites of polarized growth, defining Fry as a regulated scaffold for NDR-kinase-dependent morphogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation from wing discs plus in vivo live imaging of GFP-tagged Fry and null-rescue transgenes in Drosophila\",\n      \"pmids\": [\"20406475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the transient Fry-Trc interaction not resolved\", \"Cargo or transport machinery directed by Fry not identified\", \"No structural characterization of the Fry-Trc complex\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"To define what cellular processes Fry controls, loss-of-function genetics placed Fry/Trc upstream of F-actin levels, cell shape, differentiation timing, and DE-Cadherin/mwh expression, and distinguished this from the Warts/Yorkie tumor suppressor pathway.\",\n      \"evidence\": \"Drosophila trc/fry loss-of-function mutants with phalloidin and immunostaining readouts and yorkie epistasis\",\n      \"pmids\": [\"20211163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking Fry to DE-Cadherin/mwh transcription unknown\", \"Direct effectors downstream of the Fry/Trc module not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Asking whether FRY has a disease-relevant role, genetic mapping in rats identified Fry as a mammary carcinoma susceptibility candidate that is downregulated in tumors, implicating FRY as a tumor suppressor.\",\n      \"evidence\": \"Linkage/backcross mapping (LOD ~8.6), cDNA cloning, SNP analysis between rat strains, and expression analysis in tumors and human breast carcinoma lines\",\n      \"pmids\": [\"24023717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect of the candidate SNPs not reconstituted\", \"Causality of FRY loss in tumorigenesis not directly tested in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To test FRY function in mammalian tissue, conditional knockout and overexpression showed FRY is required for pregnancy-associated lobuloalveolar development and suppresses breast cancer cell proliferation via Hippo/YAP activation, connecting the conserved scaffold to mammalian morphogenesis and growth control.\",\n      \"evidence\": \"Cre-loxP conditional knockout mouse with mammary histology, ectopic FRY expression in MDA-MB-231 and BT474 cells with proliferation assays, and genome-wide transcriptomics\",\n      \"pmids\": [\"31824855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FRY and Hippo/YAP components not defined\", \"Whether mammalian FRY acts through an NDR kinase as in Drosophila not established here\", \"Mechanism of the lobuloalveolar defect unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FRY mechanistically activates Hippo/YAP signaling and whether its mammalian functions depend on the NDR-kinase partnership established in Drosophila remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified direct biochemical link between mammalian FRY and Hippo/YAP components\", \"NDR kinase partner for mammalian FRY not characterized in the corpus\", \"No structural or domain-level mechanism for FRY scaffold function\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"Trc\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}