{"gene":"FLII","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1997,"finding":"Human FLII encodes a 1269-residue protein containing an N-terminal leucine-rich repeat (LRR) domain and a C-terminal gelsolin-like actin-binding domain, with 58% amino acid identity to Drosophila Flightless I; FLII mRNA is most highly expressed in muscle, consistent with the flight-muscle function of the Drosophila ortholog.","method":"cDNA cloning, nucleotide sequencing, Northern blot expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing and domain identification in a single focused study with expression validation; structural inference from sequence but no in vitro biochemical reconstitution of domain activity","pmids":["9177775"],"is_preprint":false},{"year":1999,"finding":"The LRR domain of C. elegans FLI-1 (FLII ortholog) directly binds activated Ras with high affinity (Kd = 11 nM) and suppresses the heat-shock-sensitive phenotype of yeast bearing activated RAS2, while the gelsolin-like domain exhibits Ca2+-independent G-actin binding, F-actin binding, and F-actin severing activities.","method":"In vitro binding assay (Kd measurement), yeast genetic suppression assay, in vitro actin-binding and F-actin severing assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro biochemical assays (binding affinity, actin severing) combined with in vivo genetic suppression, establishing two distinct domain activities","pmids":["10092519"],"is_preprint":false},{"year":2006,"finding":"Human Flightless I (Fli-I/FLII) functions as a transcriptional coactivator; it inhibits beta-catenin/LEF1-dependent transcription, while its binding partner FLAP1 activates it. FLAP1 interacts directly with beta-catenin, GRIP1, and p300, and Fli-I disrupts the synergy between FLAP1, p300, and beta-catenin, placing FLII as a negative regulator of Wnt/beta-catenin signaling.","method":"Co-immunoprecipitation, reporter gene (transient transfection) transcription assays, siRNA knockdown of endogenous FLAP1","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping and functional transcription assays in a single lab with multiple orthogonal methods (Co-IP + reporter assays + RNAi)","pmids":["16990252"],"is_preprint":false},{"year":2016,"finding":"FLII (flightless-1 homologue) interacts with activated Rac1 and mediates pro-migratory signaling downstream of the GEF P-Rex1 (but not Tiam1), modulating cell contraction in a RhoA-ROCK-independent manner; P-Rex1 stimulates Rac1–FLII interaction to enhance cell migration.","method":"Mass spectrometry-based Rac1 interactome profiling, co-immunoprecipitation, cell migration assays with siRNA knockdown, pharmacological inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, quantitative MS interactome, loss-of-function (siRNA) with defined migratory phenotype, and GEF-specific context established using multiple orthogonal methods","pmids":["26887924"],"is_preprint":false},{"year":2011,"finding":"Overexpression of Flii (FLII) in a murine autoimmune collagen VII (ColVII) epidermolysis bullosa model worsened skin blistering, while reduced Flii expression decreased blister severity, elevated integrin expression, improved ColVII production, and reduced α-SMA, TGF-β1, and Smad2/3 levels; Flii-deficient fibroblasts showed impaired collagen gel contraction that was restored by TGF-β1, demonstrating an interplay between FLII and TGF-β1 signaling in skin integrity.","method":"Murine Flii allele crosses with ColVII EBA model and ColVII hypomorphic mice, in vitro collagen gel contraction assay with Flii-deficient fibroblasts, immunohistochemistry and Western blot","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function and gain-of-function genetic models with specific cellular phenotype readout; single lab, in vivo and in vitro corroborating methods","pmids":["21984127"],"is_preprint":false}],"current_model":"FLII (Flightless I) is a multidomain actin-remodeling protein whose gelsolin-like C-terminal domain severs and binds F-actin in a Ca2+-independent manner, whose LRR domain directly binds activated Ras, and which functions as a transcriptional coregulator (inhibiting Wnt/beta-catenin signaling and acting as a nuclear receptor coactivator); additionally, FLII interacts with activated Rac1 downstream of P-Rex1 to promote cell migration via RhoA/ROCK-independent cytoskeletal remodeling, and regulates skin/dermal integrity through modulation of TGF-β1–Smad signaling."},"narrative":{"mechanistic_narrative":"FLII (Flightless I) is a multidomain actin-remodeling protein and transcriptional coregulator that couples cytoskeletal dynamics to signaling at the actin cytoskeleton, the nucleus, and the plasma membrane [PMID:9177775, PMID:10092519]. Its bipartite architecture combines an N-terminal leucine-rich repeat (LRR) domain with a C-terminal gelsolin-like actin-binding domain [PMID:9177775]; the gelsolin-like domain binds G-actin and F-actin and severs filaments in a Ca2+-independent manner, while the LRR domain directly binds activated Ras with high affinity and suppresses activated-RAS phenotypes [PMID:10092519]. In the nucleus, FLII acts as a transcriptional coregulator that inhibits beta-catenin/LEF1-dependent transcription, disrupting the synergy between its activating partner FLAP1, p300, and beta-catenin, thereby negatively regulating Wnt/beta-catenin signaling [PMID:16990252]. At the cell periphery, FLII interacts with activated Rac1 and drives pro-migratory cytoskeletal remodeling downstream of the GEF P-Rex1 in a RhoA/ROCK-independent fashion [PMID:26887924]. FLII also modulates skin and dermal integrity through interplay with TGF-beta1–Smad signaling, where its expression level controls blistering severity, integrin and collagen VII production, and fibroblast collagen gel contraction [PMID:21984127].","teleology":[{"year":1997,"claim":"Establishing the human gene's domain architecture defined FLII as a candidate dual-function protein bridging signaling and the cytoskeleton, before any biochemical activity was known.","evidence":"cDNA cloning, sequencing, and Northern blot expression analysis identifying an LRR domain, a gelsolin-like domain, and muscle-enriched expression","pmids":["9177775"],"confidence":"Medium","gaps":["Domain activities inferred from sequence homology, not biochemically reconstituted","Functional consequence of muscle-enriched expression not tested"]},{"year":1999,"claim":"Direct biochemical assignment of activity to each domain showed the LRR binds activated Ras and the gelsolin-like domain severs actin, defining FLII as a physical link between Ras signaling and actin remodeling.","evidence":"In vitro Kd binding measurement, yeast genetic suppression of activated RAS2, and in vitro actin-binding/severing assays on the C. elegans ortholog FLI-1","pmids":["10092519"],"confidence":"High","gaps":["Performed on the C. elegans ortholog; conservation of activity in human FLII inferred","Cellular consequence of Ras binding not established"]},{"year":2006,"claim":"Identifying FLII as a transcriptional coregulator extended its role from the cytoskeleton into nuclear control of Wnt/beta-catenin signaling.","evidence":"Co-immunoprecipitation, reporter transcription assays, and siRNA knockdown of FLAP1 mapping FLII as an inhibitor of beta-catenin/LEF1 transcription opposed by FLAP1","pmids":["16990252"],"confidence":"Medium","gaps":["Mechanism of FLII nuclear recruitment to target promoters not defined","Single-lab interaction mapping without orthogonal structural validation"]},{"year":2011,"claim":"Genetic gain- and loss-of-function in a skin blistering model linked FLII expression level to dermal integrity through TGF-beta1–Smad signaling.","evidence":"Murine Flii allele crosses with a collagen VII epidermolysis bullosa model, fibroblast collagen gel contraction assays, immunohistochemistry, and Western blot","pmids":["21984127"],"confidence":"Medium","gaps":["Direct molecular link between FLII and the TGF-beta1–Smad pathway not biochemically resolved","Whether the actin or transcriptional activity of FLII drives the skin phenotype not separated"]},{"year":2016,"claim":"Identifying FLII as a Rac1 effector placed it in a specific GEF-defined migratory pathway, distinguishing its cytoskeletal role from generic RhoA/ROCK contraction.","evidence":"Mass spectrometry Rac1 interactome, reciprocal Co-IP, siRNA migration assays, and pharmacological inhibition establishing P-Rex1–Rac1–FLII pro-migratory signaling","pmids":["26887924"],"confidence":"High","gaps":["Structural basis of the Rac1–FLII interaction not resolved","Whether actin severing by the gelsolin domain executes the migratory phenotype not directly tested"]},{"year":null,"claim":"How FLII integrates its actin-severing, small-GTPase-binding, and transcriptional coregulatory activities into a unified cellular program remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model coupling LRR GTPase binding to gelsolin-domain actin severing","Mechanism of nuclear/cytoplasmic partitioning between transcriptional and cytoskeletal roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]}],"complexes":[],"partners":["RAC1","P-REX1","FLAP1","CTNNB1","RAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13045","full_name":"Protein flightless-1 homolog","aliases":[],"length_aa":1269,"mass_kda":144.8,"function":"Is a regulator of actin polymerization, required for proper myofibril organization and regulation of the length of sarcomeric thin filaments (By similarity). It also plays a role in the assembly of cardiomyocyte cell adhesion complexes (By similarity). Regulates cytoskeletal rearrangements involved in cytokinesis and cell migration, by inhibiting Rac1-dependent paxillin phosphorylation (By similarity). May play a role as coactivator in transcriptional activation by hormone-activated nuclear receptors (NR) and acts in cooperation with NCOA2 and CARM1 (PubMed:14966289). Involved in estrogen hormone signaling","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cell projection, podosome; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q13045/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FLII","classification":"Not Classified","n_dependent_lines":434,"n_total_lines":1208,"dependency_fraction":0.35927152317880795},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"MYL12A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FLII","total_profiled":1310},"omim":[{"mim_id":"620635","title":"CARDIOMYOPATHY, DILATED, 2J; CMD2J","url":"https://www.omim.org/entry/620635"},{"mim_id":"614043","title":"LEUCINE-RICH REPEAT IN FLII-INTERACTING PROTEIN 2; LRRFIP2","url":"https://www.omim.org/entry/614043"},{"mim_id":"611377","title":"BRACHYDACTYLY, TYPE B2; BDB2","url":"https://www.omim.org/entry/611377"},{"mim_id":"603256","title":"LEUCINE-RICH REPEAT IN FLII-INTERACTING PROTEIN 1; LRRFIP1","url":"https://www.omim.org/entry/603256"},{"mim_id":"601052","title":"PEPTIDYL-PROLYL CIS/TRANS ISOMERASE, NIMA-INTERACTING, 1; PIN1","url":"https://www.omim.org/entry/601052"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":239.7}],"url":"https://www.proteinatlas.org/search/FLII"},"hgnc":{"alias_symbol":["FLI","FLIL","Fli1","MGC39265"],"prev_symbol":[]},"alphafold":{"accession":"Q13045","domains":[{"cath_id":"3.80.10.10","chopping":"260-382","consensus_level":"medium","plddt":90.3172,"start":260,"end":382},{"cath_id":"3.40.20.10","chopping":"494-602","consensus_level":"medium","plddt":89.4921,"start":494,"end":602},{"cath_id":"3.40.20.10","chopping":"621-707","consensus_level":"medium","plddt":88.3016,"start":621,"end":707},{"cath_id":"3.40.20.10","chopping":"725-746_768-835","consensus_level":"high","plddt":85.3087,"start":725,"end":835},{"cath_id":"3.40.20.10","chopping":"1160-1257","consensus_level":"high","plddt":84.1598,"start":1160,"end":1257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13045","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13045-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13045-F1-predicted_aligned_error_v6.png","plddt_mean":80.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FLII","jax_strain_url":"https://www.jax.org/strain/search?query=FLII"},"sequence":{"accession":"Q13045","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13045.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13045/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13045"}},"corpus_meta":[{"pmid":"16234507","id":"PMC_16234507","title":"Immunohistochemical 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immunoreactivity (FLI) in brainstem and decreases FLI in sensory cortex.","date":"1989","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2515410","citation_count":61,"is_preprint":false},{"pmid":"26848860","id":"PMC_26848860","title":"Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26848860","citation_count":60,"is_preprint":false},{"pmid":"12054792","id":"PMC_12054792","title":"Intrinsic membrane targeting of the flagellar export ATPase FliI: interaction with acidic phospholipids and FliH.","date":"2002","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12054792","citation_count":58,"is_preprint":false},{"pmid":"10092519","id":"PMC_10092519","title":"Characterization of a novel Ras-binding protein Ce-FLI-1 comprising leucine-rich repeats and gelsolin-like domains.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10092519","citation_count":52,"is_preprint":false},{"pmid":"25714720","id":"PMC_25714720","title":"A new player at the flagellar motor: FliL controls both motor output and bias.","date":"2015","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/25714720","citation_count":51,"is_preprint":false},{"pmid":"17121899","id":"PMC_17121899","title":"Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17121899","citation_count":48,"is_preprint":false},{"pmid":"37875710","id":"PMC_37875710","title":"Fatty liver index (FLI): more than a marker of hepatic steatosis.","date":"2023","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37875710","citation_count":47,"is_preprint":false},{"pmid":"7591257","id":"PMC_7591257","title":"EWS-FLI-1 and EWS-ERG chimeric mRNAs in Ewing's sarcoma and primitive neuroectodermal tumor.","date":"1995","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7591257","citation_count":46,"is_preprint":false},{"pmid":"29091716","id":"PMC_29091716","title":"Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29091716","citation_count":46,"is_preprint":false},{"pmid":"22111876","id":"PMC_22111876","title":"Interaction between FliI ATPase and a flagellar chaperone FliT during bacterial flagellar protein export.","date":"2011","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22111876","citation_count":45,"is_preprint":false},{"pmid":"20889747","id":"PMC_20889747","title":"The flagellar protein FliL is essential for swimming in Rhodobacter sphaeroides.","date":"2010","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/20889747","citation_count":44,"is_preprint":false},{"pmid":"22829238","id":"PMC_22829238","title":"Drug-mediated inhibition of Fli-1 for the treatment of leukemia.","date":"2012","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/22829238","citation_count":43,"is_preprint":false},{"pmid":"30890608","id":"PMC_30890608","title":"Structure of Vibrio FliL, a New Stomatin-like Protein That Assists the Bacterial Flagellar Motor Function.","date":"2019","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/30890608","citation_count":42,"is_preprint":false},{"pmid":"36124657","id":"PMC_36124657","title":"EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36124657","citation_count":42,"is_preprint":false},{"pmid":"26103585","id":"PMC_26103585","title":"FliL associates with the stator to support torque generation of the sodium-driven polar flagellar motor of Vibrio.","date":"2015","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26103585","citation_count":42,"is_preprint":false},{"pmid":"11431376","id":"PMC_11431376","title":"The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11431376","citation_count":42,"is_preprint":false},{"pmid":"9286988","id":"PMC_9286988","title":"Identification of the fliI and fliJ components of the Caulobacter flagellar type III protein secretion system.","date":"1997","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9286988","citation_count":40,"is_preprint":false},{"pmid":"21321929","id":"PMC_21321929","title":"The c-Abl tyrosine kinase controls protein kinase Cδ-induced Fli-1 phosphorylation in human dermal fibroblasts.","date":"2011","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/21321929","citation_count":40,"is_preprint":false},{"pmid":"20665663","id":"PMC_20665663","title":"The Ewing's sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation.","date":"2010","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20665663","citation_count":39,"is_preprint":false},{"pmid":"16969112","id":"PMC_16969112","title":"Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16969112","citation_count":39,"is_preprint":false},{"pmid":"9177775","id":"PMC_9177775","title":"Genomic structure, evolution, and expression of human FLII, a gelsolin and leucine-rich-repeat family member: overlap with LLGL.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9177775","citation_count":38,"is_preprint":false},{"pmid":"15367440","id":"PMC_15367440","title":"Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15367440","citation_count":38,"is_preprint":false},{"pmid":"23527175","id":"PMC_23527175","title":"BCL11B is up-regulated by EWS/FLI and contributes to the transformed phenotype in Ewing sarcoma.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23527175","citation_count":38,"is_preprint":false},{"pmid":"35412146","id":"PMC_35412146","title":"Current insights into the role of Fli-1 in hematopoiesis and malignant transformation.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35412146","citation_count":37,"is_preprint":false},{"pmid":"25098295","id":"PMC_25098295","title":"The Fli-1 transcription factor regulates the expression of CCL5/RANTES.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25098295","citation_count":37,"is_preprint":false},{"pmid":"35046042","id":"PMC_35046042","title":"The flagellar motor protein FliL forms a scaffold of circumferentially positioned rings required for stator activation.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35046042","citation_count":36,"is_preprint":false},{"pmid":"11580247","id":"PMC_11580247","title":"Proteolytic analysis of the FliH/FliI complex, the ATPase component of the type III flagellar export apparatus of Salmonella.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11580247","citation_count":36,"is_preprint":false},{"pmid":"30741932","id":"PMC_30741932","title":"Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30741932","citation_count":36,"is_preprint":false},{"pmid":"19665005","id":"PMC_19665005","title":"ATP-induced FliI hexamerization facilitates bacterial flagellar protein export.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19665005","citation_count":35,"is_preprint":false},{"pmid":"8157599","id":"PMC_8157599","title":"Characterization of the fliL gene in the flagellar regulon of Escherichia coli and Salmonella typhimurium.","date":"1994","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8157599","citation_count":34,"is_preprint":false},{"pmid":"21984127","id":"PMC_21984127","title":"Overexpression of the Flii gene increases dermal-epidermal blistering in an autoimmune ColVII mouse model of epidermolysis bullosa acquisita.","date":"2011","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21984127","citation_count":34,"is_preprint":false},{"pmid":"18927503","id":"PMC_18927503","title":"Microsatellites are EWS/FLI response elements: genomic \"junk\" is EWS/FLI's treasure.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18927503","citation_count":34,"is_preprint":false},{"pmid":"18785112","id":"PMC_18785112","title":"Fli-1 expression in malignant melanoma.","date":"2008","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/18785112","citation_count":33,"is_preprint":false},{"pmid":"15273724","id":"PMC_15273724","title":"Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15273724","citation_count":32,"is_preprint":false},{"pmid":"21084965","id":"PMC_21084965","title":"FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma.","date":"2011","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/21084965","citation_count":32,"is_preprint":false},{"pmid":"26916245","id":"PMC_26916245","title":"FliH and FliI ensure efficient energy coupling of flagellar type III protein export in Salmonella.","date":"2016","source":"MicrobiologyOpen","url":"https://pubmed.ncbi.nlm.nih.gov/26916245","citation_count":31,"is_preprint":false},{"pmid":"23320737","id":"PMC_23320737","title":"The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice.","date":"2013","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23320737","citation_count":31,"is_preprint":false},{"pmid":"25968649","id":"PMC_25968649","title":"Mutations in the Borrelia burgdorferi Flagellar Type III Secretion System Genes fliH and fliI Profoundly Affect Spirochete Flagellar Assembly, Morphology, Motility, Structure, and Cell Division.","date":"2015","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/25968649","citation_count":31,"is_preprint":false},{"pmid":"9444955","id":"PMC_9444955","title":"Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9444955","citation_count":31,"is_preprint":false},{"pmid":"34976713","id":"PMC_34976713","title":"One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma.","date":"2021","source":"Journal of bone oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34976713","citation_count":30,"is_preprint":false},{"pmid":"30387554","id":"PMC_30387554","title":"Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30387554","citation_count":30,"is_preprint":false},{"pmid":"30053030","id":"PMC_30053030","title":"Fli-1 Governs Pericyte Dysfunction in a Murine Model of Sepsis.","date":"2018","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30053030","citation_count":29,"is_preprint":false},{"pmid":"26807198","id":"PMC_26807198","title":"The role of FLI-1-EWS, a fusion gene reciprocal to EWS-FLI-1, in Ewing sarcoma.","date":"2015","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26807198","citation_count":29,"is_preprint":false},{"pmid":"22749036","id":"PMC_22749036","title":"EWS/FLI-responsive GGAA microsatellites exhibit polymorphic differences between European and African populations.","date":"2012","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22749036","citation_count":29,"is_preprint":false},{"pmid":"25331431","id":"PMC_25331431","title":"Loss of FliL alters Proteus mirabilis surface sensing and temperature-dependent swarming.","date":"2014","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/25331431","citation_count":28,"is_preprint":false},{"pmid":"34145397","id":"PMC_34145397","title":"The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34145397","citation_count":28,"is_preprint":false},{"pmid":"9231413","id":"PMC_9231413","title":"A flagellar-specific ATPase (FliI) is necessary for flagellar export in Helicobacter pylori.","date":"1997","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/9231413","citation_count":28,"is_preprint":false},{"pmid":"23222728","id":"PMC_23222728","title":"Activity of Proteus mirabilis FliL is viscosity dependent and requires extragenic DNA.","date":"2012","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/23222728","citation_count":26,"is_preprint":false},{"pmid":"11991951","id":"PMC_11991951","title":"Ets-1 regulates fli-1 expression in endothelial cells. Identification of ETS binding sites in the fli-1 gene promoter.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11991951","citation_count":26,"is_preprint":false},{"pmid":"14567998","id":"PMC_14567998","title":"EWS/FLI function varies in different cellular backgrounds.","date":"2003","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/14567998","citation_count":26,"is_preprint":false},{"pmid":"35038582","id":"PMC_35038582","title":"Suppression of Fli-1 protects against pericyte loss and cognitive deficits in Alzheimer's disease.","date":"2022","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35038582","citation_count":25,"is_preprint":false},{"pmid":"19642105","id":"PMC_19642105","title":"EWS/Fli-1 chimeric fusion gene upregulates vascular endothelial growth factor-A.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19642105","citation_count":24,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49298,"output_tokens":2169,"usd":0.090215,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8237,"output_tokens":2305,"usd":0.049405,"stage2_stop_reason":"end_turn"},"total_usd":0.13962,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the human FLII gene (Flightless I, a gelsolin/LRR domain protein involved in actin remodeling) versus:\n- FLI-1/FLI1 (ETS transcription factor, a different gene)\n- FliI (bacterial flagellar ATPase)\n- FLI (Fos-like immunoreactivity, a completely different concept)\n- FLI (Fatty Liver Index)\n\nThe query gene is FLII (Flightless I homolog), with aliases FLI, FLIL, MGC39265. This is the actin-remodeling protein with gelsolin and LRR domains.\n\nKey papers about FLII:\n- PMID 9177775: Genomic structure of human FLII - gelsolin-like actin binding domain and LRR domain\n- PMID 10092519: Ce-FLI-1 - LRR domain binds Ras, gelsolin domain binds/severs actin\n- PMID 16990252: Fli-I as coactivator for nuclear receptor transcription; FLAP1 interaction; beta-catenin regulation\n- PMID 26887924: FLII (flightless-1 homologue) in Rac1-driven cell migration\n- PMID 21984127: Flii in skin blistering/wound repair\n\nThe FLI-1/FLI1 ETS transcription factor papers are about a DIFFERENT gene (FLI1, chromosome 11q24). FLII is on chromosome 17p11.2. These are distinct genes - FLI1 is not an alias for FLII.\n\nWait - the HGNC aliases given are FLI, FLIL, MGC39265. I need to check if \"FLI\" as an alias for FLII could mean some of the FLI-1 papers are actually about FLII. However, FLI-1 (Friend leukemia integration 1) is a completely different gene from FLII (Flightless I). The alias \"FLI\" for FLII refers to the Drosophila flightless-I homolog designation, not to FLI-1 the ETS factor. The context of these papers (ETS domain, transcription factor, Ewing sarcoma translocation) is completely incompatible with FLII (actin/gelsolin protein). These are symbol collisions.\n\nPapers genuinely about FLII: 9177775, 10092519, 16990252, 26887924, 21984127\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Human FLII encodes a 1269-residue protein containing an N-terminal leucine-rich repeat (LRR) domain and a C-terminal gelsolin-like actin-binding domain, with 58% amino acid identity to Drosophila Flightless I; FLII mRNA is most highly expressed in muscle, consistent with the flight-muscle function of the Drosophila ortholog.\",\n      \"method\": \"cDNA cloning, nucleotide sequencing, Northern blot expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing and domain identification in a single focused study with expression validation; structural inference from sequence but no in vitro biochemical reconstitution of domain activity\",\n      \"pmids\": [\"9177775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The LRR domain of C. elegans FLI-1 (FLII ortholog) directly binds activated Ras with high affinity (Kd = 11 nM) and suppresses the heat-shock-sensitive phenotype of yeast bearing activated RAS2, while the gelsolin-like domain exhibits Ca2+-independent G-actin binding, F-actin binding, and F-actin severing activities.\",\n      \"method\": \"In vitro binding assay (Kd measurement), yeast genetic suppression assay, in vitro actin-binding and F-actin severing assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro biochemical assays (binding affinity, actin severing) combined with in vivo genetic suppression, establishing two distinct domain activities\",\n      \"pmids\": [\"10092519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human Flightless I (Fli-I/FLII) functions as a transcriptional coactivator; it inhibits beta-catenin/LEF1-dependent transcription, while its binding partner FLAP1 activates it. FLAP1 interacts directly with beta-catenin, GRIP1, and p300, and Fli-I disrupts the synergy between FLAP1, p300, and beta-catenin, placing FLII as a negative regulator of Wnt/beta-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene (transient transfection) transcription assays, siRNA knockdown of endogenous FLAP1\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping and functional transcription assays in a single lab with multiple orthogonal methods (Co-IP + reporter assays + RNAi)\",\n      \"pmids\": [\"16990252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FLII (flightless-1 homologue) interacts with activated Rac1 and mediates pro-migratory signaling downstream of the GEF P-Rex1 (but not Tiam1), modulating cell contraction in a RhoA-ROCK-independent manner; P-Rex1 stimulates Rac1–FLII interaction to enhance cell migration.\",\n      \"method\": \"Mass spectrometry-based Rac1 interactome profiling, co-immunoprecipitation, cell migration assays with siRNA knockdown, pharmacological inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, quantitative MS interactome, loss-of-function (siRNA) with defined migratory phenotype, and GEF-specific context established using multiple orthogonal methods\",\n      \"pmids\": [\"26887924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of Flii (FLII) in a murine autoimmune collagen VII (ColVII) epidermolysis bullosa model worsened skin blistering, while reduced Flii expression decreased blister severity, elevated integrin expression, improved ColVII production, and reduced α-SMA, TGF-β1, and Smad2/3 levels; Flii-deficient fibroblasts showed impaired collagen gel contraction that was restored by TGF-β1, demonstrating an interplay between FLII and TGF-β1 signaling in skin integrity.\",\n      \"method\": \"Murine Flii allele crosses with ColVII EBA model and ColVII hypomorphic mice, in vitro collagen gel contraction assay with Flii-deficient fibroblasts, immunohistochemistry and Western blot\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function and gain-of-function genetic models with specific cellular phenotype readout; single lab, in vivo and in vitro corroborating methods\",\n      \"pmids\": [\"21984127\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FLII (Flightless I) is a multidomain actin-remodeling protein whose gelsolin-like C-terminal domain severs and binds F-actin in a Ca2+-independent manner, whose LRR domain directly binds activated Ras, and which functions as a transcriptional coregulator (inhibiting Wnt/beta-catenin signaling and acting as a nuclear receptor coactivator); additionally, FLII interacts with activated Rac1 downstream of P-Rex1 to promote cell migration via RhoA/ROCK-independent cytoskeletal remodeling, and regulates skin/dermal integrity through modulation of TGF-β1–Smad signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FLII (Flightless I) is a multidomain actin-remodeling protein and transcriptional coregulator that couples cytoskeletal dynamics to signaling at the actin cytoskeleton, the nucleus, and the plasma membrane [#0, #1]. Its bipartite architecture combines an N-terminal leucine-rich repeat (LRR) domain with a C-terminal gelsolin-like actin-binding domain [#0]; the gelsolin-like domain binds G-actin and F-actin and severs filaments in a Ca2+-independent manner, while the LRR domain directly binds activated Ras with high affinity and suppresses activated-RAS phenotypes [#1]. In the nucleus, FLII acts as a transcriptional coregulator that inhibits beta-catenin/LEF1-dependent transcription, disrupting the synergy between its activating partner FLAP1, p300, and beta-catenin, thereby negatively regulating Wnt/beta-catenin signaling [#2]. At the cell periphery, FLII interacts with activated Rac1 and drives pro-migratory cytoskeletal remodeling downstream of the GEF P-Rex1 in a RhoA/ROCK-independent fashion [#3]. FLII also modulates skin and dermal integrity through interplay with TGF-beta1\\u2013Smad signaling, where its expression level controls blistering severity, integrin and collagen VII production, and fibroblast collagen gel contraction [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the human gene's domain architecture defined FLII as a candidate dual-function protein bridging signaling and the cytoskeleton, before any biochemical activity was known.\",\n      \"evidence\": \"cDNA cloning, sequencing, and Northern blot expression analysis identifying an LRR domain, a gelsolin-like domain, and muscle-enriched expression\",\n      \"pmids\": [\"9177775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain activities inferred from sequence homology, not biochemically reconstituted\", \"Functional consequence of muscle-enriched expression not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Direct biochemical assignment of activity to each domain showed the LRR binds activated Ras and the gelsolin-like domain severs actin, defining FLII as a physical link between Ras signaling and actin remodeling.\",\n      \"evidence\": \"In vitro Kd binding measurement, yeast genetic suppression of activated RAS2, and in vitro actin-binding/severing assays on the C. elegans ortholog FLI-1\",\n      \"pmids\": [\"10092519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed on the C. elegans ortholog; conservation of activity in human FLII inferred\", \"Cellular consequence of Ras binding not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying FLII as a transcriptional coregulator extended its role from the cytoskeleton into nuclear control of Wnt/beta-catenin signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, reporter transcription assays, and siRNA knockdown of FLAP1 mapping FLII as an inhibitor of beta-catenin/LEF1 transcription opposed by FLAP1\",\n      \"pmids\": [\"16990252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FLII nuclear recruitment to target promoters not defined\", \"Single-lab interaction mapping without orthogonal structural validation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic gain- and loss-of-function in a skin blistering model linked FLII expression level to dermal integrity through TGF-beta1\\u2013Smad signaling.\",\n      \"evidence\": \"Murine Flii allele crosses with a collagen VII epidermolysis bullosa model, fibroblast collagen gel contraction assays, immunohistochemistry, and Western blot\",\n      \"pmids\": [\"21984127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FLII and the TGF-beta1\\u2013Smad pathway not biochemically resolved\", \"Whether the actin or transcriptional activity of FLII drives the skin phenotype not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying FLII as a Rac1 effector placed it in a specific GEF-defined migratory pathway, distinguishing its cytoskeletal role from generic RhoA/ROCK contraction.\",\n      \"evidence\": \"Mass spectrometry Rac1 interactome, reciprocal Co-IP, siRNA migration assays, and pharmacological inhibition establishing P-Rex1\\u2013Rac1\\u2013FLII pro-migratory signaling\",\n      \"pmids\": [\"26887924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Rac1\\u2013FLII interaction not resolved\", \"Whether actin severing by the gelsolin domain executes the migratory phenotype not directly tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FLII integrates its actin-severing, small-GTPase-binding, and transcriptional coregulatory activities into a unified cellular program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model coupling LRR GTPase binding to gelsolin-domain actin severing\", \"Mechanism of nuclear/cytoplasmic partitioning between transcriptional and cytoskeletal roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAC1\", \"P-Rex1\", \"FLAP1\", \"CTNNB1\", \"RAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}