{"gene":"FRY","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2009,"finding":"FRY (Furry) acts as a scaffold protein in the NDR1 kinase activation complex: it binds to both NDR1 and MOB2, synergistically activating NDR1 kinase activity together with MOB2, and acts downstream of MST2. FRY also binds to microtubules and localizes to the mitotic spindle. Depletion of FRY, NDR1, or MST2 in HeLa cells causes mitotic chromosome misalignment, and this misalignment in MST2-depleted cells is rescued by expression of constitutively active NDR1, placing FRY in the MST2→FRY/MOB2→NDR1 pathway required for accurate chromosome alignment at metaphase.","method":"siRNA knockdown of FRY, NDR1, and MST2 in HeLa cells; co-immunoprecipitation demonstrating FRY-NDR1 and FRY-MOB2 interactions; in vitro kinase assays; microtubule-binding assays; epistasis rescue experiment with active NDR1","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, kinase assay, epistasis rescue, and localization with functional consequence in a single study","pmids":["19327996"],"is_preprint":false},{"year":2012,"finding":"FRY (Furry) promotes bipolar mitotic spindle formation by facilitating Aurora A-mediated phosphorylation of Polo-like kinase 1 (Plk1) at Thr-210. FRY binds to the polo-box domain (PBD) of Plk1 in a manner dependent on CDK1-mediated phosphorylation of FRY at Thr-2516, and also binds to Aurora A. Depletion of FRY reduces Plk1 kinase activity, reduces Thr-210-phosphorylated Plk1 at spindle poles, and causes centrosome/centriole splitting and multipolar spindle formation.","method":"Co-immunoprecipitation of FRY with Plk1 and Aurora A; site-directed mutagenesis of FRY Thr-2516; in vitro kinase assays measuring Plk1 activity; siRNA depletion with spindle and centrosome phenotype analysis by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis, kinase assay, and loss-of-function phenotype with mechanistic rescue in single study","pmids":["22753416"],"is_preprint":false},{"year":2013,"finding":"FRY (Furry) promotes acetylation of α-tubulin (Lys40) on mitotic spindle microtubules by binding to and inhibiting the tubulin deacetylase SIRT2 preferentially in mitotic cells. The N-terminal region of FRY is sufficient for SIRT2 binding and SIRT2 inhibition in cell-free assays. Depletion of FRY significantly reduces spindle microtubule acetylation, while expression of the N-terminal FRY fragment causes hyperacetylation in both mitotic and interphase cells. The SIRT2 inhibitor AGK2 rescues the reduction in acetylation caused by FRY depletion, confirming that FRY promotes spindle MT acetylation through SIRT2 inhibition.","method":"Co-immunoprecipitation of FRY with SIRT2; cell-free tubulin deacetylase inhibition assay; siRNA depletion with immunofluorescence quantification of acetylated tubulin; ectopic expression of N-terminal FRY fragment; chemical rescue with SIRT2 inhibitor AGK2","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1/2 — cell-free enzymatic inhibition assay plus Co-IP, loss-of-function, gain-of-function, and chemical rescue in single study","pmids":["23886946"],"is_preprint":false},{"year":2010,"finding":"Drosophila Fry (furry) protein interacts with the NDR kinase Tricornered (Trc); full-length Fry and Trc can be co-immunoprecipitated from wing discs. Fry is highly mobile in bristles and dendrites and accumulates at the distal tip of growing bristles, suggesting a role in directing intracellular transport for polarized growth. An N-terminal fragment of Fry shows near-complete co-localization with Trc, whereas full-length Fry shows only partial co-localization, indicating that the Fry–Trc interaction is transient and regulated. Fry is required for normal morphogenesis of epidermal cell extensions and dendritic tiling.","method":"Co-immunoprecipitation from Drosophila wing disc lysates; in vivo live imaging with GFP-tagged Fry; transgenic rescue of fry null lethality; FRAP-like mobility analysis in bristles","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus live localization with functional context, single lab","pmids":["20406475"],"is_preprint":false},{"year":2010,"finding":"In Drosophila wing cells, the NDR kinase Trc and its binding partner Fry regulate cell shape, cellular F-actin levels, timing of differentiation, and the expression of multiple wing hairs and DE-Cadherin prior to terminal differentiation. Fry regulates expression of DE-cadherin and multiple wing hairs (mwh). The effects of Wts (the other Drosophila NDR kinase) on all these processes are mediated through Yorkie transcription factor, distinguishing the Trc/Fry pathway from the Wts/Mats pathway.","method":"Genetic loss-of-function analysis (trc and fry mutations); F-actin staining; immunostaining for DE-Cadherin and wing hair markers; epistasis with yorkie","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined phenotypic readouts, single lab","pmids":["20211163"],"is_preprint":false},{"year":2019,"finding":"Mammalian FRY is required for normal mammary gland development specifically during pregnancy: conditional knockout of Fry in mouse mammary glands results in more lateral buds and smaller, undistended lobuloalveoli during late pregnancy, while virgin mammary gland development is unaffected. Ectopic expression of FRY in breast cancer cell lines (MDA-MB-231 and BT474) suppresses cell growth and proliferation, alters cell morphology, and activates the Hippo/YAP pathway as revealed by genome-wide transcriptomic analysis, suggesting FRY interacts with protein kinase signaling relevant to Hippo signaling.","method":"Conditional Cre-loxP mammary gland-specific Fry knockout mice; mammary gland histology during pregnancy; ectopic FRY expression in cancer cell lines with proliferation assays; genome-wide RNA-seq transcriptomic analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo conditional KO with histological phenotype plus in vitro gain-of-function with transcriptomic pathway analysis, single lab","pmids":["31824855"],"is_preprint":false},{"year":2013,"finding":"The rat Fry gene, ortholog of Drosophila furry, was identified as a candidate mammary carcinoma susceptibility (Mcs30) gene on rat chromosome 12. The complete 13 kb Fry mRNA was cloned and sequenced, revealing ~90% amino acid conservation among eutherian mammals. Two non-synonymous SNPs distinguish the carcinoma-resistant Copenhagen and susceptible Fischer 344 rat strains, 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 mapping (backcross, LOD ~8.6); full mRNA cloning and sequencing; SNP analysis between rat strains; RT-PCR/expression analysis in mammary tumors and human cancer cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — genetic linkage plus expression analysis; mechanistic interpretation is inferential but supported by evolutionary conservation analysis and SNP functional prediction","pmids":["24023717"],"is_preprint":false}],"current_model":"FRY (Furry) is an evolutionarily conserved scaffold protein that operates at the nexus of multiple mitotic regulatory pathways: it scaffolds the MST2→NDR1 kinase activation complex (binding NDR1 and MOB2 to promote NDR1 activity required for accurate chromosome alignment), facilitates Aurora A-mediated Plk1 phosphorylation at Thr-210 to maintain bipolar spindle integrity (binding Plk1's polo-box domain in a CDK1-phosphorylation-dependent manner), and promotes α-tubulin acetylation on spindle microtubules by binding to and inhibiting the deacetylase SIRT2; additionally, 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 pathway."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing FRY as a mitotic scaffold resolved how the conserved MST–NDR signaling cascade is organized in mammalian cells: FRY bridges NDR1 and MOB2, synergistically activating NDR1 downstream of MST2 to ensure chromosome alignment.","evidence":"Co-IP, in vitro kinase assays, siRNA epistasis rescue with constitutively active NDR1 in HeLa cells","pmids":["19327996"],"confidence":"High","gaps":["Structural basis of FRY–NDR1–MOB2 ternary complex unknown","Whether FRY scaffolds NDR2 similarly is untested","Regulation of FRY recruitment to the spindle not defined"]},{"year":2010,"claim":"Drosophila studies demonstrated that the Fry–Trc (NDR kinase) interaction is conserved and dynamically regulated, with Fry directing polarized cell morphogenesis independently of the Wts/Yorkie branch of Hippo signaling.","evidence":"Co-IP from wing disc lysates; live GFP imaging showing Fry mobility and tip accumulation; genetic epistasis separating Trc/Fry from Wts/Yorkie in wing cells","pmids":["20406475","20211163"],"confidence":"Medium","gaps":["Whether the transient nature of Fry–Trc interaction is phosphorylation-regulated remains unclear","Direct transcriptional targets downstream of Fry/Trc not identified in mammals"]},{"year":2012,"claim":"Identification of FRY as a CDK1-phosphorylation-dependent adaptor bridging Aurora A to Plk1 revealed a second mitotic axis through which FRY ensures bipolar spindle formation, explaining why FRY depletion causes centrosome splitting and multipolar spindles.","evidence":"Co-IP of FRY with Plk1 and Aurora A; site-directed mutagenesis of FRY Thr-2516; in vitro kinase assays; siRNA depletion with spindle phenotype analysis","pmids":["22753416"],"confidence":"High","gaps":["Whether FRY simultaneously scaffolds NDR1 and Plk1 complexes or these are mutually exclusive is unknown","No structural model of FRY–PBD interaction exists"]},{"year":2013,"claim":"Discovery that FRY directly binds and inhibits the tubulin deacetylase SIRT2 established a third mitotic function — promotion of spindle microtubule acetylation — mechanistically distinct from its kinase-scaffolding roles.","evidence":"Cell-free deacetylase inhibition assay with N-terminal FRY fragment; Co-IP; siRNA depletion with chemical rescue by SIRT2 inhibitor AGK2","pmids":["23886946"],"confidence":"High","gaps":["Functional consequence of reduced spindle acetylation for chromosome segregation fidelity not directly tested","Whether SIRT2 inhibition and NDR1 scaffolding are coordinated through the same FRY molecule is unknown"]},{"year":2013,"claim":"Genetic linkage and expression analysis identified FRY as a candidate mammary carcinoma susceptibility gene, with reduced expression in rat mammary tumors and human breast cancer cell lines, motivating investigation of FRY's tumor-suppressive role.","evidence":"Backcross linkage mapping (LOD ~8.6) in rat; SNP analysis; RT-PCR expression profiling in mammary tumors and human cell lines","pmids":["24023717"],"confidence":"Medium","gaps":["Causative role of identified SNPs not functionally validated","Mechanism linking FRY loss to tumor susceptibility not established in this study"]},{"year":2019,"claim":"Conditional knockout and gain-of-function experiments demonstrated that FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation through Hippo/YAP pathway activation, linking its kinase-scaffolding function to tissue-level growth control.","evidence":"Cre-loxP mammary-specific Fry knockout mice with histological analysis; ectopic FRY expression in MDA-MB-231 and BT474 with proliferation assays and RNA-seq","pmids":["31824855"],"confidence":"Medium","gaps":["Direct FRY–YAP biochemical interaction not demonstrated","Whether tumor suppression depends on NDR1 scaffolding versus other FRY functions is untested","Relevance to human breast cancer patients not established"]},{"year":null,"claim":"How FRY integrates its three known mitotic functions (NDR1 scaffolding, Plk1 activation, SIRT2 inhibition) temporally during mitotic progression, and whether its tumor-suppressive activity in mammary tissue operates through these same mechanisms, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural or cryo-EM model of FRY or its complexes exists","Post-translational regulation of FRY beyond CDK1 phosphorylation at Thr-2516 is unexplored","Whether FRY loss contributes to aneuploidy in cancer through its mitotic functions is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,5]}],"complexes":[],"partners":["NDR1","MOB2","MST2","PLK1","AURKA","SIRT2"],"other_free_text":[]},"mechanistic_narrative":"FRY (Protein furry homolog) is an evolutionarily conserved scaffold protein that coordinates multiple mitotic regulatory pathways to ensure accurate cell division. It scaffolds the MST2→NDR1 kinase activation complex by binding both NDR1 and MOB2, synergistically activating NDR1 kinase activity required for proper chromosome alignment at metaphase [PMID:19327996]. FRY also facilitates Aurora A–mediated phosphorylation of Plk1 at Thr-210 through CDK1-dependent binding to Plk1's polo-box domain, maintaining bipolar spindle integrity [PMID:22753416], and promotes α-tubulin acetylation on spindle microtubules by directly binding and inhibiting the deacetylase SIRT2 [PMID:23886946]. In vivo, FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation in part through Hippo/YAP pathway activation [PMID:31824855]."},"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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Full-length Fry and Trc show only partial co-localization in growing bristles, whereas an amino-terminal fragment of Fry co-localizes closely with Trc, suggesting the interaction is transient and regulated.\",\n      \"method\": \"Co-immunoprecipitation from wing discs; GFP-tagged transgene rescue of fry null lethality; in vivo live imaging of GFP-Fry in bristles and dendrites\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with tagged transgene validation in a single study; no independent replication reported\",\n      \"pmids\": [\"20406475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila wing cells, the NDR kinase Trc (ortholog of mammalian LATS/NDR) and the large Fry protein regulate cell shape, F-actin levels, timing of terminal differentiation, DE-Cadherin expression, and multiple wing hair formation. The effects of Wts (the other NDR kinase) on these processes are mediated through the Yorkie transcription factor, whereas Trc regulates DE-cadherin and mwh independently.\",\n      \"method\": \"Loss-of-function genetic analysis (null mutations in trc and fry); immunostaining for F-actin, DE-Cadherin; epistasis with yorkie\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined cellular phenotypes and genetic epistasis in Drosophila; single lab\",\n      \"pmids\": [\"20211163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mammalian FRY is required for mammary gland lobuloalveolar development during pregnancy; conditional knockout of Fry in mouse mammary glands results in more lateral buds and smaller, undistended lobuloalveoli during late pregnancy. Ectopic FRY expression in breast cancer cell lines (MDA-MB-231 and BT474) suppresses growth and proliferation, and transcriptomic analysis indicates FRY activates the Hippo/YAP pathway.\",\n      \"method\": \"Conditional knockout (Cre-loxP) in mouse mammary gland; ectopic 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 — in vivo conditional KO with defined morphological phenotype plus in vitro OE with pathway analysis; single lab\",\n      \"pmids\": [\"31824855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The rat Fry gene (ortholog of Drosophila furry) was mapped as a candidate mammary carcinoma susceptibility (Mcs30) gene on rat chromosome 12. Two non-synonymous SNPs distinguishing resistant (Cop) and susceptible (F344) rat strains were identified, one of which creates a putative de novo phosphorylation site. Fry expression is reduced in the majority of rat mammary tumors, and FRY activity appears reduced in human breast carcinoma cell lines.\",\n      \"method\": \"Genetic linkage mapping (backcross); cloning and sequencing of full-length Fry mRNA; SNP analysis; expression profiling in tumors vs. normal tissue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic mapping and expression correlation; no direct enzymatic or biochemical mechanism established\",\n      \"pmids\": [\"24023717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRY (Furry) encodes a large scaffolding protein that physically interacts with NDR family kinases (Trc/LATS orthologs) in a transient, regulated manner to control polarized cell growth, actin cytoskeleton organization, and cell shape in Drosophila epidermal cells; in mammals, FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation at least in part by activating the Hippo/YAP signaling pathway.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nFrom the main 100 papers: Papers [1]-[100] are overwhelmingly about fish aquaculture, fish immunology, virology, toxicology, etc. — using \"fry\" as the word meaning \"juvenile fish.\" These are EXCLUDE (not about the FRY gene). \n\nPapers [25] and [51] describe Drosophila Fry/furry protein (Trc/Fry, NDR kinase context) — these are KEEP as orthologs consistent with the mammalian FRY gene.\n\nFrom gene2pubmed-curated papers:\n- [14] PMID:19327996 — MST2/Furry/NDR1 kinase in mitotic chromosome alignment — KEEP\n- [19] PMID:23886946 — Furry promotes microtubule acetylation by inhibiting SIRT2 — KEEP\n- [23] PMID:22753416 — Furry promotes Aurora A-mediated Plk1 activation — KEEP\n- [75] PMID:31824855 — FRY role in mammary gland development and breast cancer — KEEP\n- [76] PMID:24023717 — Fry as candidate Mcs gene, rat mammary carcinogenesis — KEEP\n- [2] PMID:28514442 — BioPlex 2.0 interactome (FRY appears as interaction partner) — weak signal, but it's a proteome-wide study; marginal. EXCLUDE (no specific mechanistic finding about FRY)\n- [5] PMID:33961781 — BioPlex 3.0 — same issue, EXCLUDE\n- [1] PMID:21906983 — ubiquitinome — EXCLUDE (no specific FRY finding)\n- [3] PMID:29507755 — VIRMA/m6A — EXCLUDE\n- [4] PMID:14702039 — cDNA sequencing — EXCLUDE\n- [6] PMID:21873635 — GO propagation — EXCLUDE\n- [7] PMID:24880342 — lung cancer GWAS — EXCLUDE\n- [8] PMID:23382691 — IgG glycosylation GWAS — EXCLUDE\n- [9] PMID:23602568 — CMGC kinase interactome — EXCLUDE\n- [10] PMID:16196087 — ubiquitin proteome — EXCLUDE\n- [11] PMID:32989298 — AURORA-A PROTAC — EXCLUDE\n- [12] PMID:20379614 — smoking cessation — EXCLUDE\n- [13] PMID:30021884 — histone XL-MS — EXCLUDE\n- [15] PMID:31586073 — midbody interactome — EXCLUDE\n- [16] PMID:15057823 — chr13 sequence — EXCLUDE\n- [17] PMID:23443559 — LGALS3BP centrosome — EXCLUDE\n- [18] PMID:12586822 — Tamalin scaffold — EXCLUDE\n- [20] PMID:25189868 — BP GWAS — EXCLUDE\n- [21] PMID:9847074 — genome sequence — EXCLUDE\n- [22] PMID:8812419 — BRCA2 region transcription map — EXCLUDE\n- [24] PMID:29676528 — RNF123/lamin — EXCLUDE\n- [25] PMID:25907116 — SARS-CoV P6 — EXCLUDE\n- [26] PMID:19773279 — benzene toxicity GWAS — EXCLUDE\n- [27] PMID:37689310 — DDB1-CUL4 — EXCLUDE\n- [28] PMID:38334954 — XL-MS PDX — EXCLUDE\n- [29] PMID:35914814 — Chr21 PPIs — EXCLUDE\n- [30] PMID:40437099 — EndoMAP — EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"FRY (Furry) acts as a scaffold protein in the NDR1 kinase activation complex: it binds to both NDR1 and MOB2, synergistically activating NDR1 kinase activity together with MOB2, and acts downstream of MST2. FRY also binds to microtubules and localizes to the mitotic spindle. Depletion of FRY, NDR1, or MST2 in HeLa cells causes mitotic chromosome misalignment, and this misalignment in MST2-depleted cells is rescued by expression of constitutively active NDR1, placing FRY in the MST2→FRY/MOB2→NDR1 pathway required for accurate chromosome alignment at metaphase.\",\n      \"method\": \"siRNA knockdown of FRY, NDR1, and MST2 in HeLa cells; co-immunoprecipitation demonstrating FRY-NDR1 and FRY-MOB2 interactions; in vitro kinase assays; microtubule-binding assays; epistasis rescue experiment with active NDR1\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, kinase assay, epistasis rescue, and localization with functional consequence in a single study\",\n      \"pmids\": [\"19327996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FRY (Furry) promotes bipolar mitotic spindle formation by facilitating Aurora A-mediated phosphorylation of Polo-like kinase 1 (Plk1) at Thr-210. FRY binds to the polo-box domain (PBD) of Plk1 in a manner dependent on CDK1-mediated phosphorylation of FRY at Thr-2516, and also binds to Aurora A. Depletion of FRY reduces Plk1 kinase activity, reduces Thr-210-phosphorylated Plk1 at spindle poles, and causes centrosome/centriole splitting and multipolar spindle formation.\",\n      \"method\": \"Co-immunoprecipitation of FRY with Plk1 and Aurora A; site-directed mutagenesis of FRY Thr-2516; in vitro kinase assays measuring Plk1 activity; siRNA depletion with spindle and centrosome phenotype analysis by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis, kinase assay, and loss-of-function phenotype with mechanistic rescue in single study\",\n      \"pmids\": [\"22753416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FRY (Furry) promotes acetylation of α-tubulin (Lys40) on mitotic spindle microtubules by binding to and inhibiting the tubulin deacetylase SIRT2 preferentially in mitotic cells. The N-terminal region of FRY is sufficient for SIRT2 binding and SIRT2 inhibition in cell-free assays. Depletion of FRY significantly reduces spindle microtubule acetylation, while expression of the N-terminal FRY fragment causes hyperacetylation in both mitotic and interphase cells. The SIRT2 inhibitor AGK2 rescues the reduction in acetylation caused by FRY depletion, confirming that FRY promotes spindle MT acetylation through SIRT2 inhibition.\",\n      \"method\": \"Co-immunoprecipitation of FRY with SIRT2; cell-free tubulin deacetylase inhibition assay; siRNA depletion with immunofluorescence quantification of acetylated tubulin; ectopic expression of N-terminal FRY fragment; chemical rescue with SIRT2 inhibitor AGK2\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — cell-free enzymatic inhibition assay plus Co-IP, loss-of-function, gain-of-function, and chemical rescue in single study\",\n      \"pmids\": [\"23886946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Fry (furry) protein interacts with the NDR kinase Tricornered (Trc); full-length Fry and Trc can be co-immunoprecipitated from wing discs. Fry is highly mobile in bristles and dendrites and accumulates at the distal tip of growing bristles, suggesting a role in directing intracellular transport for polarized growth. An N-terminal fragment of Fry shows near-complete co-localization with Trc, whereas full-length Fry shows only partial co-localization, indicating that the Fry–Trc interaction is transient and regulated. Fry is required for normal morphogenesis of epidermal cell extensions and dendritic tiling.\",\n      \"method\": \"Co-immunoprecipitation from Drosophila wing disc lysates; in vivo live imaging with GFP-tagged Fry; transgenic rescue of fry null lethality; FRAP-like mobility analysis in bristles\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus live localization with functional context, single lab\",\n      \"pmids\": [\"20406475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila wing cells, the NDR kinase Trc and its binding partner Fry regulate cell shape, cellular F-actin levels, timing of differentiation, and the expression of multiple wing hairs and DE-Cadherin prior to terminal differentiation. Fry regulates expression of DE-cadherin and multiple wing hairs (mwh). The effects of Wts (the other Drosophila NDR kinase) on all these processes are mediated through Yorkie transcription factor, distinguishing the Trc/Fry pathway from the Wts/Mats pathway.\",\n      \"method\": \"Genetic loss-of-function analysis (trc and fry mutations); F-actin staining; immunostaining for DE-Cadherin and wing hair markers; epistasis with yorkie\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"20211163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mammalian FRY is required for normal mammary gland development specifically during pregnancy: conditional knockout of Fry in mouse mammary glands results in more lateral buds and smaller, undistended lobuloalveoli during late pregnancy, while virgin mammary gland development is unaffected. Ectopic expression of FRY in breast cancer cell lines (MDA-MB-231 and BT474) suppresses cell growth and proliferation, alters cell morphology, and activates the Hippo/YAP pathway as revealed by genome-wide transcriptomic analysis, suggesting FRY interacts with protein kinase signaling relevant to Hippo signaling.\",\n      \"method\": \"Conditional Cre-loxP mammary gland-specific Fry knockout mice; mammary gland histology during pregnancy; ectopic FRY expression in cancer cell lines with proliferation assays; genome-wide RNA-seq transcriptomic analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional KO with histological phenotype plus in vitro gain-of-function with transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"31824855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The rat Fry gene, ortholog of Drosophila furry, was identified as a candidate mammary carcinoma susceptibility (Mcs30) gene on rat chromosome 12. The complete 13 kb Fry mRNA was cloned and sequenced, revealing ~90% amino acid conservation among eutherian mammals. Two non-synonymous SNPs distinguish the carcinoma-resistant Copenhagen and susceptible Fischer 344 rat strains, 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 mapping (backcross, LOD ~8.6); full mRNA cloning and sequencing; SNP analysis between rat strains; RT-PCR/expression analysis in mammary tumors and human cancer cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic linkage plus expression analysis; mechanistic interpretation is inferential but supported by evolutionary conservation analysis and SNP functional prediction\",\n      \"pmids\": [\"24023717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRY (Furry) is an evolutionarily conserved scaffold protein that operates at the nexus of multiple mitotic regulatory pathways: it scaffolds the MST2→NDR1 kinase activation complex (binding NDR1 and MOB2 to promote NDR1 activity required for accurate chromosome alignment), facilitates Aurora A-mediated Plk1 phosphorylation at Thr-210 to maintain bipolar spindle integrity (binding Plk1's polo-box domain in a CDK1-phosphorylation-dependent manner), and promotes α-tubulin acetylation on spindle microtubules by binding to and inhibiting the deacetylase SIRT2; additionally, 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 pathway.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FRY encodes a large scaffolding protein that physically interacts with NDR family kinases to regulate cell polarity, cytoskeletal organization, and tissue morphogenesis. In Drosophila, FRY (Furry) binds the NDR kinase Tricornered (Trc) in a transient, regulated manner and functions together with Trc to control cell shape, F-actin levels, DE-Cadherin expression, and terminal differentiation in wing epithelial cells, operating through a pathway distinct from Yorkie-dependent Warts signaling [PMID:20406475, PMID:20211163]. In mammals, conditional knockout of Fry in mouse mammary glands disrupts lobuloalveolar development during pregnancy, and ectopic FRY expression suppresses breast cancer cell proliferation through activation of the Hippo/YAP pathway [PMID:31824855].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that Fry physically associates with the NDR kinase Trc and that this interaction is transient and spatially regulated resolved how Fry engages its kinase partner in vivo rather than acting as a constitutive scaffold.\",\n      \"evidence\": \"Co-immunoprecipitation from Drosophila wing discs; GFP-tagged transgene imaging in bristles and dendrites\",\n      \"pmids\": [\"20406475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reciprocal endogenous-level Co-IP or independent replication reported\",\n        \"Structural basis for the transient nature of the Fry–Trc interaction is unknown\",\n        \"Whether mammalian FRY interacts with NDR1/NDR2 or LATS1/LATS2 in the same manner is untested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that Fry and Trc jointly control cell shape, F-actin, and DE-Cadherin through a pathway independent of Yorkie defined a Trc/Fry-specific branch of NDR kinase signaling in epithelial morphogenesis.\",\n      \"evidence\": \"Loss-of-function genetic analysis of fry and trc null mutants in Drosophila wing cells; epistasis tests with yorkie\",\n      \"pmids\": [\"20211163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct substrates of the Trc kinase downstream of Fry are unidentified\",\n        \"Mechanism by which Fry/Trc regulate F-actin independently of Warts/Yorkie is unknown\",\n        \"Single-lab study in one tissue; generality across other Drosophila epithelia not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping Fry as a candidate mammary carcinoma susceptibility gene in the rat and observing reduced FRY expression in tumors provided the first link between FRY and cancer, though no direct causal mechanism was demonstrated.\",\n      \"evidence\": \"Genetic linkage mapping in rat backcross; SNP analysis; expression profiling of tumors versus normal mammary tissue\",\n      \"pmids\": [\"24023717\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Correlational evidence only — no functional rescue or knockout to confirm causality\",\n        \"The functional significance of the candidate de novo phosphorylation site SNP is untested\",\n        \"Whether reduced FRY expression is a cause or consequence of tumor progression is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that mammalian FRY is required for mammary lobuloalveolar morphogenesis and suppresses breast cancer cell growth via Hippo/YAP pathway activation extended FRY's morphogenetic role from Drosophila to mammals and linked it to a defined tumor-suppressive signaling axis.\",\n      \"evidence\": \"Conditional Cre-loxP knockout in mouse mammary gland; ectopic overexpression in breast cancer cell lines with proliferation assays and transcriptomic analysis\",\n      \"pmids\": [\"31824855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FRY activates the Hippo pathway by directly binding LATS kinases (analogous to Trc) or through an indirect mechanism is unknown\",\n        \"Transcriptomic analysis shows pathway-level activation but no direct biochemical target of FRY in the Hippo cascade is identified\",\n        \"Single-lab study; independent confirmation of the mammary phenotype is absent\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of direct mammalian FRY binding partners in the Hippo pathway, the structural basis for FRY's scaffolding function, and whether FRY acts as a bona fide tumor suppressor across multiple cancer types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct mammalian FRY–NDR/LATS kinase physical interaction has been demonstrated\",\n        \"No structural or domain-resolution analysis of FRY exists\",\n        \"In vivo tumor suppression (e.g., increased tumorigenesis in Fry-knockout mice) has not been shown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"Trc\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"FRY (Protein furry homolog) is an evolutionarily conserved scaffold protein that coordinates multiple mitotic regulatory pathways to ensure accurate cell division. It scaffolds the MST2→NDR1 kinase activation complex by binding both NDR1 and MOB2, synergistically activating NDR1 kinase activity required for proper chromosome alignment at metaphase [PMID:19327996]. FRY also facilitates Aurora A–mediated phosphorylation of Plk1 at Thr-210 through CDK1-dependent binding to Plk1's polo-box domain, maintaining bipolar spindle integrity [PMID:22753416], and promotes α-tubulin acetylation on spindle microtubules by directly binding and inhibiting the deacetylase SIRT2 [PMID:23886946]. In vivo, FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation in part through Hippo/YAP pathway activation [PMID:31824855].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing FRY as a mitotic scaffold resolved how the conserved MST–NDR signaling cascade is organized in mammalian cells: FRY bridges NDR1 and MOB2, synergistically activating NDR1 downstream of MST2 to ensure chromosome alignment.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, siRNA epistasis rescue with constitutively active NDR1 in HeLa cells\",\n      \"pmids\": [\"19327996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of FRY–NDR1–MOB2 ternary complex unknown\",\n        \"Whether FRY scaffolds NDR2 similarly is untested\",\n        \"Regulation of FRY recruitment to the spindle not defined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Drosophila studies demonstrated that the Fry–Trc (NDR kinase) interaction is conserved and dynamically regulated, with Fry directing polarized cell morphogenesis independently of the Wts/Yorkie branch of Hippo signaling.\",\n      \"evidence\": \"Co-IP from wing disc lysates; live GFP imaging showing Fry mobility and tip accumulation; genetic epistasis separating Trc/Fry from Wts/Yorkie in wing cells\",\n      \"pmids\": [\"20406475\", \"20211163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the transient nature of Fry–Trc interaction is phosphorylation-regulated remains unclear\",\n        \"Direct transcriptional targets downstream of Fry/Trc not identified in mammals\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of FRY as a CDK1-phosphorylation-dependent adaptor bridging Aurora A to Plk1 revealed a second mitotic axis through which FRY ensures bipolar spindle formation, explaining why FRY depletion causes centrosome splitting and multipolar spindles.\",\n      \"evidence\": \"Co-IP of FRY with Plk1 and Aurora A; site-directed mutagenesis of FRY Thr-2516; in vitro kinase assays; siRNA depletion with spindle phenotype analysis\",\n      \"pmids\": [\"22753416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FRY simultaneously scaffolds NDR1 and Plk1 complexes or these are mutually exclusive is unknown\",\n        \"No structural model of FRY–PBD interaction exists\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that FRY directly binds and inhibits the tubulin deacetylase SIRT2 established a third mitotic function — promotion of spindle microtubule acetylation — mechanistically distinct from its kinase-scaffolding roles.\",\n      \"evidence\": \"Cell-free deacetylase inhibition assay with N-terminal FRY fragment; Co-IP; siRNA depletion with chemical rescue by SIRT2 inhibitor AGK2\",\n      \"pmids\": [\"23886946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of reduced spindle acetylation for chromosome segregation fidelity not directly tested\",\n        \"Whether SIRT2 inhibition and NDR1 scaffolding are coordinated through the same FRY molecule is unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic linkage and expression analysis identified FRY as a candidate mammary carcinoma susceptibility gene, with reduced expression in rat mammary tumors and human breast cancer cell lines, motivating investigation of FRY's tumor-suppressive role.\",\n      \"evidence\": \"Backcross linkage mapping (LOD ~8.6) in rat; SNP analysis; RT-PCR expression profiling in mammary tumors and human cell lines\",\n      \"pmids\": [\"24023717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causative role of identified SNPs not functionally validated\",\n        \"Mechanism linking FRY loss to tumor susceptibility not established in this study\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional knockout and gain-of-function experiments demonstrated that FRY is required for mammary lobuloalveolar development during pregnancy and suppresses breast cancer cell proliferation through Hippo/YAP pathway activation, linking its kinase-scaffolding function to tissue-level growth control.\",\n      \"evidence\": \"Cre-loxP mammary-specific Fry knockout mice with histological analysis; ectopic FRY expression in MDA-MB-231 and BT474 with proliferation assays and RNA-seq\",\n      \"pmids\": [\"31824855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct FRY–YAP biochemical interaction not demonstrated\",\n        \"Whether tumor suppression depends on NDR1 scaffolding versus other FRY functions is untested\",\n        \"Relevance to human breast cancer patients not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FRY integrates its three known mitotic functions (NDR1 scaffolding, Plk1 activation, SIRT2 inhibition) temporally during mitotic progression, and whether its tumor-suppressive activity in mammary tissue operates through these same mechanisms, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural or cryo-EM model of FRY or its complexes exists\",\n        \"Post-translational regulation of FRY beyond CDK1 phosphorylation at Thr-2516 is unexplored\",\n        \"Whether FRY loss contributes to aneuploidy in cancer through its mitotic functions is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NDR1\",\n      \"MOB2\",\n      \"MST2\",\n      \"PLK1\",\n      \"AURKA\",\n      \"SIRT2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}