Affinage

FLII

Protein flightless-1 homolog · UniProt Q13045

Round 2 corrected
Length
1269 aa
Mass
144.8 kDa
Annotated
2026-04-28
130 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLII (Protein flightless-1 homolog) is an actin-remodeling protein that functions as a transcriptional coactivator for nuclear receptor targets and as a repressor of Wnt/β-catenin signaling by disrupting the FLAP1–p300–β-catenin complex (PMID:16990252). FLII regulates skin integrity and blistering severity in epidermolysis bullosa: overexpression exacerbates blistering in murine collagen VII models, while reduced FLII expression improves collagen VII production, elevates integrin expression, and attenuates TGF-β1/Smad2/3-driven fibrosis (PMID:21984127).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2006 Medium

    Establishing that FLII operates as a dual transcriptional regulator — coactivating nuclear receptor targets while suppressing Wnt/β-catenin/LEF1/TCF-dependent transcription through disruption of the FLAP1–p300–β-catenin complex — answered how a single gelsolin-family protein could modulate both nuclear receptor and Wnt signaling outputs.

    Evidence Transient transfection reporter assays, co-immunoprecipitation, GST pull-down, and siRNA knockdown of FLAP1 in mammalian cell lines

    PMID:16990252

    Open questions at the time
    • No structural or in vivo validation of the FLII–FLAP1–p300–β-catenin disruption mechanism
    • Endogenous chromatin context and genome-wide target genes of FLII transcriptional regulation are undefined
    • Whether FLII actin-binding and transcriptional activities are coupled or independent remains unresolved
  2. 2011 High

    Demonstrating that FLII dosage directly controls skin blistering severity in epidermolysis bullosa models — with overexpression worsening and haploinsufficiency ameliorating disease through modulation of collagen VII, integrin expression, and TGF-β1/Smad2/3 signaling — established FLII as a pathogenic mediator in EB and linked its function to fibrotic remodeling in vivo.

    Evidence Flii allelic series (overexpression and heterozygous knockout) in autoimmune collagen VII EBA and ColVII hypomorphic mouse models, collagen gel contraction assays, immunofluorescence, and Western blot

    PMID:21984127

    Open questions at the time
    • Direct molecular mechanism by which FLII regulates TGF-β1/Smad2/3 signaling is not delineated
    • Whether FLII transcriptional co-regulation (Wnt/nuclear receptor) contributes to the blistering phenotype is untested
    • Therapeutic applicability of FLII reduction in human epidermolysis bullosa has not been demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The relationship between FLII's actin-remodeling activity, its transcriptional co-regulatory roles, and its in vivo control of skin integrity remains mechanistically unintegrated — it is unknown whether these represent a single pathway or separable functions.
  • No domain-specific mutations separating actin-binding from transcriptional functions have been tested in vivo
  • Genome-wide transcriptional targets of FLII in skin and other tissues are uncharacterized
  • Structural basis for FLII interaction with FLAP1, p300, and β-catenin is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 2 GO:0140110 transcription regulator activity 1 R-HSA-1643685 Disease 1
Partners
CTNNB1EP300FLAP1GRIP1

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Flightless-I (Fli-I/FLII) functions as a coactivator for nuclear receptor-mediated transcription and inhibits beta-catenin/LEF1/TCF-dependent transcription. Fli-I was found to disrupt the synergy between FLAP1 (Fli-I leucine rich repeat associated protein 1), p300, and beta-catenin, thereby suppressing Wnt target gene activation. FLAP1 directly interacted with beta-catenin, GRIP1, and p300 and enhanced their transcriptional activity, while Fli-I counteracted this. The opposing activities of Fli-I and FLAP1 were proposed as a regulatory mechanism for Wnt/beta-catenin signaling, with Fli-I mutations potentially causing developmental defects (e.g., Drosophila flightless phenotype) through dysregulation of this pathway. Transient transfection reporter assays, co-immunoprecipitation, GST pull-down, siRNA knockdown of endogenous FLAP1 Nucleic acids research Medium 16990252
2011 FLII (Flightless I) is a novel mediator of skin blistering in epidermolysis bullosa (EB). Overexpression of Flii in mice exacerbated blistering severity in an autoimmune collagen VII (ColVII) model of EB acquisita, while reduced Flii expression decreased blister severity, elevated integrin expression, and improved ColVII production. Flii-deficient fibroblasts showed reduced ability to contract collagen gels in vitro, and TGF-β1 restored collagen contraction in Flii-deficient cells, indicating an interplay between Flii and the TGF-β1/Smad2/3 signaling pathway. Reduced Flii also decreased α-SMA and TGF-β1/Smad2/3 expression in blistered skin, suggesting Flii promotes fibrosis. Murine Flii allelic series (Flii overexpressing and Flii+/- mice), autoimmune ColVII EBA mouse model, ColVII hypomorphic genetic mouse model, collagen gel contraction assays, immunofluorescence, Western blot The Journal of pathology High 21984127

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2005 Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 661 16234507
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2000 Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 296 10981960
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2011 A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 269 21654808
2018 EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma. Nature 254 29513652
2008 Distinct roles of the FliI ATPase and proton motive force in bacterial flagellar protein export. Nature 245 18216858
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
1991 Salmonella typhimurium mutants defective in flagellar filament regrowth and sequence similarity of FliI to F0F1, vacuolar, and archaebacterial ATPase subunits. Journal of bacteriology 184 1646201
2007 Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development. Proceedings of the National Academy of Sciences of the United States of America 183 17962413
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
1993 EWS/Fli-1 chimeric protein is a transcriptional activator. Cancer research 159 7503813
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2018 EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma. Cancer cell 134 29358035
2007 Structural similarity between the flagellar type III ATPase FliI and F1-ATPase subunits. Proceedings of the National Academy of Sciences of the United States of America 124 17202259
2010 Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 120 20547696
2003 Functional cross-antagonism between transcription factors FLI-1 and EKLF. Molecular and cellular biology 114 12556498
2014 The ets transcription factor Fli-1 in development, cancer and disease. Oncogene 113 24909161
2006 Oncoprotein EWS-FLI1 activity is enhanced by RNA helicase A. Cancer research 112 16740692
2000 The role of Fli-1 in normal cell function and malignant transformation. Oncogene 105 11175364
2003 Oligomerization and activation of the FliI ATPase central to bacterial flagellum assembly. Molecular microbiology 94 12787361
2021 TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma. Cancer cell 90 34329586
1999 FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. Oncogene 90 10102630
1994 Caulobacter flagellar function, but not assembly, requires FliL, a non-polarly localized membrane protein present in all cell types. Journal of molecular biology 81 7932752
2009 EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma. Cancer research 75 19920188
2005 Ewing's sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. Future oncology (London, England) 72 16556028
2008 FliL is essential for swarming: motor rotation in absence of FliL fractures the flagellar rod in swarmer cells of Salmonella enterica. Molecular microbiology 71 18284590
2011 A novel gene inactivation system reveals altered periplasmic flagellar orientation in a Borrelia burgdorferi fliL mutant. Journal of bacteriology 68 21441522
2017 Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma. The Journal of experimental medicine 67 28232470
2005 Role of FliF and FliI of Listeria monocytogenes in flagellar assembly and pathogenicity. Infection and immunity 65 16113269
2014 Assembly dynamics and the roles of FliI ATPase of the bacterial flagellar export apparatus. Scientific reports 64 25284201
2008 The transcription factor Fli-1 modulates marginal zone and follicular B cell development in mice. Journal of immunology (Baltimore, Md. : 1950) 63 18641300
2006 Interplay of Fli-I and FLAP1 for regulation of beta-catenin dependent transcription. Nucleic acids research 62 16990252
2018 Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition. PLoS genetics 61 30500808
1989 Trigeminal nerve section induces Fos-like immunoreactivity (FLI) in brainstem and decreases FLI in sensory cortex. Brain research. Molecular brain research 61 2515410
2021 SPOP and OTUD7A Control EWS-FLI1 Protein Stability to Govern Ewing Sarcoma Growth. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 59 34060252
2016 Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting. Oncotarget 59 26848860
2005 Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood 51 15994290
2004 Recombinant EWS-FLI1 oncoprotein activates transcription. Biochemistry 51 15491164
2015 A new player at the flagellar motor: FliL controls both motor output and bias. mBio 50 25714720
2015 EWS/FLI1 Target Genes and Therapeutic Opportunities in Ewing Sarcoma. Frontiers in oncology 49 26258070
2010 Downstream EWS/FLI1 - upstream Ewing's sarcoma. Genome medicine 49 20156317
2013 Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma. Blood 48 23926301
2019 Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner. Clinical cancer research : an official journal of the American Association for Cancer Research 45 30723142
2011 Interaction between FliI ATPase and a flagellar chaperone FliT during bacterial flagellar protein export. Molecular microbiology 45 22111876
2010 The flagellar protein FliL is essential for swimming in Rhodobacter sphaeroides. Journal of bacteriology 44 20889747
2023 Fatty liver index (FLI): more than a marker of hepatic steatosis. Journal of physiology and biochemistry 43 37875710
2012 Drug-mediated inhibition of Fli-1 for the treatment of leukemia. Blood cancer journal 43 22829238
2008 EWS-Fli1 up-regulates expression of the Aurora A and Aurora B kinases. Molecular cancer research : MCR 43 19074838
2010 EWS/FLI1 oncogene activates caspase 3 transcription and triggers apoptosis in vivo. Cancer research 42 20103643
2001 The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1. Cancer research 42 11431376
2019 Structure of Vibrio FliL, a New Stomatin-like Protein That Assists the Bacterial Flagellar Motor Function. mBio 41 30890608
2023 ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation. Nature cell biology 40 36658219
1997 Identification of the fliI and fliJ components of the Caulobacter flagellar type III protein secretion system. Journal of bacteriology 40 9286988
2016 Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma. Molecular therapy : the journal of the American Society of Gene Therapy 39 27166877
2010 The Ewing's sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation. Journal of cellular biochemistry 39 20665663
2014 Fli1 acts downstream of Etv2 to govern cell survival and vascular homeostasis via positive autoregulation. Circulation research 38 24727028
2024 FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity. Nature communications 36 38816360
2019 Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis. Cell death & disease 36 30741932
2014 The Fli-1 transcription factor regulates the expression of CCL5/RANTES. Journal of immunology (Baltimore, Md. : 1950) 36 25098295
2002 EWS-FLI1 and Ewing's sarcoma: recent molecular data and new insights. Cancer biology & therapy 36 12432241
2022 The flagellar motor protein FliL forms a scaffold of circumferentially positioned rings required for stator activation. Proceedings of the National Academy of Sciences of the United States of America 35 35046042
2022 Current insights into the role of Fli-1 in hematopoiesis and malignant transformation. Cellular and molecular life sciences : CMLS 35 35412146
2017 Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis. American journal of respiratory cell and molecular biology 35 28248553
2009 ATP-induced FliI hexamerization facilitates bacterial flagellar protein export. Biochemical and biophysical research communications 35 19665005
2017 Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features. Haematologica 34 28255014
2011 Overexpression of the Flii gene increases dermal-epidermal blistering in an autoimmune ColVII mouse model of epidermolysis bullosa acquisita. The Journal of pathology 34 21984127
1994 Characterization of the fliL gene in the flagellar regulon of Escherichia coli and Salmonella typhimurium. Journal of bacteriology 34 8157599
2020 EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma. Nucleic acids research 32 33080033
2019 USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth. Scientific reports 32 30700749
2017 FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology. Blood 32 28432223
2011 FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma. Applied immunohistochemistry & molecular morphology : AIMM 32 21084965
2004 Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1. Oncogene 32 15273724
2016 FliH and FliI ensure efficient energy coupling of flagellar type III protein export in Salmonella. MicrobiologyOpen 31 26916245
2013 The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice. Immunology 31 23320737
1997 Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1. Oncogene 31 9444955
2016 Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells. The Journal of biological chemistry 30 26961871
2021 One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma. Journal of bone oncology 29 34976713
2016 Structures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1. Nucleic acids research 28 27587584
2015 Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis. The international journal of biochemistry & cell biology 28 26055516
2014 Loss of FliL alters Proteus mirabilis surface sensing and temperature-dependent swarming. Journal of bacteriology 28 25331431
2022 EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 27 35653119
2020 RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis. Science advances 27 33097530
2008 EWS/FLI1 suppresses retinoblastoma protein function and senescence in Ewing's sarcoma cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 27 18271016
2012 Activity of Proteus mirabilis FliL is viscosity dependent and requires extragenic DNA. Journal of bacteriology 26 23222728
2010 Loss of GATA1 and gain of FLI1 expression during thrombocyte maturation. Blood cells, molecules & diseases 26 20110178
2021 Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma. Cancers 25 34359682
2022 Suppression of Fli-1 protects against pericyte loss and cognitive deficits in Alzheimer's disease. Molecular therapy : the journal of the American Society of Gene Therapy 24 35038582
2022 The transcription factor Fli1 restricts the formation of memory precursor NK cells during viral infection. Nature immunology 24 35288713
2021 Fusion protein EWS-FLI1 is incorporated into a protein granule in cells. RNA (New York, N.Y.) 24 34035145
2022 The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease. The Journal of clinical investigation 23 36074578
1997 Production and characterization of mouse monoclonal antibodies to wild-type and oncogenic FLI-1 proteins. Hybridoma 23 9388029
2020 Fli1 Downregulation in Scleroderma Myeloid Cells Has Profibrotic and Proinflammatory Effects. Frontiers in immunology 22 32508810
2020 Emerging role of Fli1 in autoimmune diseases. International immunopharmacology 22 33234418
2022 Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex. Oncogene 21 36357572
2016 Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor. European journal of immunology 21 27431361
2014 EWS-FLI-1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology. Cancer 21 24415532
2020 The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation. International journal of cancer 20 31846072
2012 Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity. Frontiers in oncology 20 22973553
2006 Solid pseudopapillary neoplasms of the pancreas are associated with FLI-1 expression, but not with EWS/FLI-1 translocation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 16941013
2023 EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma. International journal of molecular sciences 19 37894854
2015 PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1. Oncotarget 19 26336820
2022 Super enhancer-LncRNA SENCR promoted cisplatin resistance and growth of NSCLC through upregulating FLI1. Journal of clinical laboratory analysis 18 35500152
2020 High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma. Cancers 18 32164354
2015 Structural Basis for Dimerization and DNA Binding of Transcription Factor FLI1. Biochemistry 18 26618620
1999 Interaction of FliI, a component of the flagellar export apparatus, with flagellin and hook protein. Biochimica et biophysica acta 18 10350613