{"gene":"FBLIM1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2003,"finding":"Migfilin (FBLIM1) localizes to cell-matrix adhesions, interacts with Mig-2 (kindlin-2 homolog UNC-112) through its C-terminal domain and with filamin through its N-terminal domain, thereby functioning as a scaffold linking cell-matrix adhesions to the actin cytoskeleton and regulating cell shape modulation.","method":"Co-immunoprecipitation, pulldown assays, siRNA knockdown, loss-of-function phenotypic analysis (cell shape modulation defects)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, and siRNA KD with defined cellular phenotype in foundational paper with >300 citations","pmids":["12679033"],"is_preprint":false},{"year":2008,"finding":"The N-terminal portion of migfilin binds all three human filamins (FLNa, FLNb, FLNc), preferentially to IgFLNa21 and more weakly to IgFLNa19 and IgFLNa22 via the CD face of the IgFLN beta-sandwich. The migfilin-filamin binding site (Pro5–Pro19) overlaps with the integrin beta tail binding site on IgFLNa21, allowing migfilin and integrin beta tails to compete for the same filamin binding surface.","method":"X-ray crystallography, NMR spectroscopy, protein-protein interaction competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure and NMR with functional validation of competitive binding mechanism","pmids":["18829455"],"is_preprint":false},{"year":2008,"finding":"Migfilin structurally interacts with filamin at the same region where integrin beta cytoplasmic tails bind, and this interaction dissociates filamin from integrin, promoting talin/integrin binding and integrin activation; migfilin thus acts as a molecular switch between filamin-mediated inhibition and talin-mediated activation of integrins.","method":"NMR structural analysis, pulldown assays, integrin activation functional assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — structural and functional reconstitution with mechanistic validation","pmids":["19074766"],"is_preprint":false},{"year":2005,"finding":"Migfilin contains an N-terminal filamin-binding domain, a central proline-rich domain, and three C-terminal LIM domains; it is recruited to cell-matrix contacts upon adhesion, colocalizes with beta-catenin at cell-cell junctions, shuttles from cytoplasm to nucleus in a process regulated by RNA splicing and calcium signaling, and interacts with VASP and the cardiac transcription factor CSX/NKX2-5.","method":"Biochemical interaction studies, live-cell imaging, domain deletion analysis, yeast two-hybrid","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 — review synthesizing primary data from multiple binding partner identification studies","pmids":["15701922"],"is_preprint":false},{"year":2006,"finding":"Migfilin interacts with vasodilator-stimulated phosphoprotein (VASP) via the VASP EVH1 domain and a single LPPPPP site in the migfilin proline-rich domain; this interaction facilitates VASP localization to cell-matrix adhesions and is required for migfilin-regulated cell migration.","method":"Co-immunoprecipitation, GST pulldown, domain mutagenesis, siRNA knockdown, cell migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis of interaction site, VASP KD rescue experiment, cellular functional readout","pmids":["16531412"],"is_preprint":false},{"year":2004,"finding":"Migfilin (Cal/FBLIM1) interacts with the cardiac transcription factor CSX/NKX2-5 via its LIM domains and the NKX2-5 homeodomain; migfilin possesses transcription-promoting activity, contains a functional nuclear export signal, shuttles to the nucleus in response to calcium, and promotes myocardial cell differentiation when accumulated in the nucleus.","method":"Yeast two-hybrid, Co-IP, in vitro binding, nuclear export signal analysis, calcium-regulated nuclear translocation assay, P19CL6 differentiation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including Co-IP, domain mapping, and functional differentiation assay","pmids":["14757752"],"is_preprint":false},{"year":2005,"finding":"Migfilin is recruited to cell-cell junctions (adherens junctions) in response to cadherin-mediated adhesion; the C-terminal LIM domains mediate this localization; migfilin associates with beta-catenin but not desmosomes at cell-cell junctions; siRNA-mediated depletion of migfilin compromises adherens junction organization and weakens cell-cell association.","method":"Immunofluorescence, immunoelectron microscopy, siRNA knockdown, domain deletion analysis, cell-cell adhesion assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence via siRNA KD and domain mapping","pmids":["15671069"],"is_preprint":false},{"year":2009,"finding":"Migfilin directly interacts with Src kinase, with the migfilin binding surface overlapping the inhibitory intramolecular interaction sites in Src; this interaction activates Src, leading to suppression of anoikis; loss of cell-ECM adhesion reduces migfilin levels and induces apoptosis, and overexpression of migfilin desensitizes cells to detachment-induced apoptosis.","method":"Co-immunoprecipitation, direct binding assays, overexpression/depletion experiments, apoptosis assays (caspase activation), Src kinase activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, Src activation assay, gain- and loss-of-function with defined apoptotic phenotype","pmids":["19833732"],"is_preprint":false},{"year":2011,"finding":"Migfilin displaces filamin from beta1 and beta3 integrins and promotes integrin activation in endothelial cells and neutrophils; filamin acts broadly as an inhibitor of integrin activation and migfilin overcomes this inhibition; migfilin depletion impairs spreading and migration of endothelial cells.","method":"Flow cytometry (integrin activation), siRNA knockdown, spreading and migration assays in primary vascular cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — functional integrin activation assay with KD in primary cells, moderate evidence from single lab","pmids":["22043318"],"is_preprint":false},{"year":2011,"finding":"NMR spectroscopy demonstrates that filamin autoinhibition of integrin-binding repeats 19 and 21 can be relieved by integrin or by migfilin via a multisite binding mechanism, with repeats 19 and 21 simultaneously engaging ligands, suggesting filamin is mechanically stretched by migfilin/integrin interaction.","method":"NMR spectroscopy, binding assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structural analysis, single lab","pmids":["21524097"],"is_preprint":false},{"year":2008,"finding":"Kindlin-1 and kindlin-2 interact with migfilin (FBLIM1) and colocalize at focal adhesions in keratinocytes; loss of kindlin-1 does not affect FBLIM1 gene expression or migfilin protein localization, indicating migfilin can function independently of kindlin-1.","method":"Co-immunoprecipitation, confocal microscopy, siRNA knockdown, immunostaining","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and imaging with functional independence established by KD","pmids":["18528435"],"is_preprint":false},{"year":2012,"finding":"Genetic inactivation of FBLIM1 (encoding FBLP-1/migfilin) in mice causes osteopenic phenotype; loss of FBLP-1 impairs BMSC adhesion, migration, growth, and survival; reduces osteoblast progenitors and differentiation; dramatically increases osteoclast differentiation; markedly elevates RANKL in null BMSCs via ERK1/2 hyperactivation; ERK1/2 inhibition suppresses the RANKL increase.","method":"Genetic knockout (mouse), primary cell culture assays (adhesion, migration, proliferation, differentiation), in vivo bone histomorphometry, western blot (RANKL, pERK), pharmacological ERK inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal cellular and in vivo phenotypic readouts plus pathway placement via ERK inhibition","pmids":["22556421"],"is_preprint":false},{"year":2012,"finding":"Migfilin promotes migration and invasion in glioma cells by positively modulating EGFR expression and activity; migfilin-mediated migration and invasion depend on EGFR-induced PLC-gamma and STAT3 signaling pathways.","method":"Immunohistochemistry, siRNA knockdown, migration/invasion assays, western blot (EGFR, PLC-gamma, STAT3 phosphorylation)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined pathway placement, single lab","pmids":["22843679"],"is_preprint":false},{"year":2012,"finding":"Migfilin inhibits esophageal cancer cell motility by promoting GSK-3beta-mediated phosphorylation and proteasomal degradation of beta-catenin; migfilin reinforces the association between beta-catenin and GSK-3beta; overexpression of beta-catenin or inhibition of GSK-3beta reverses migfilin-mediated suppression of invasion.","method":"Overexpression, siRNA knockdown, beta-catenin reporter assay, co-IP (migfilin–beta-catenin–GSK-3beta complex), proteasome inhibitor rescue, invasion assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of complex, mechanistic rescue experiments with inhibitors and mutants","pmids":["22246236"],"is_preprint":false},{"year":2013,"finding":"Kindlin-1 and kindlin-2 bind the C-terminal tandem LIM domains of migfilin; this interaction drives migfilin FA recruitment, localization, and mobility; FRAP and FRET analyses show kindlin depletion alters migfilin dynamics; when the C-terminal LIM region is deleted, the N-terminal filamin-binding region directs migfilin to actin stress fibers instead.","method":"Kindlin knockdown, biochemical pulldown, fluorescence microscopy, FRET, FRAP, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (biochemical + live-cell imaging dynamics) establishing interaction and functional consequence","pmids":["24165133"],"is_preprint":false},{"year":2015,"finding":"Src phosphorylates kindlin-2 at Y193, which enhances Src kinase activity; kindlin-2 Y193 phosphorylation is required for migfilin binding to kindlin-2 and the recruitment of migfilin to focal adhesions; this constitutes a positive feedback loop among Src, kindlin-2, and migfilin.","method":"In vitro kinase assay, phospho-specific mutant analysis, Co-IP, immunofluorescence, cell spreading and migration assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — kinase assay plus Co-IP plus functional cell assay, single lab","pmids":["26037143"],"is_preprint":false},{"year":2017,"finding":"Recessive mutations in the filamin-binding domain of FBLIM1, as well as regulatory variants ablating an enhancer, underlie chronic recurrent multifocal osteomyelitis (CRMO); the Fblim1 ortholog is the most differentially expressed gene (>20-fold downregulated) in bone marrow macrophages of the cmo mouse model.","method":"Whole-exome sequencing, Sanger sequencing, microarray expression analysis of cmo mouse BMMs, enhancer reporter assay in SaOS2 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic evidence plus reporter assay, single lab","pmids":["28301468"],"is_preprint":false},{"year":2018,"finding":"FBLIM1 knockdown in OSCC cells attenuates proliferation, migration, and invasiveness; FBLIM1 expression correlates with EGFR activity; clopidogrel treatment downregulates both EGFR and FBLIM1, phenocopying the KD effect, placing FBLIM1 upstream or co-regulatory with EGFR signaling in oral cancer.","method":"siRNA knockdown, clopidogrel pharmacological inhibition, qRT-PCR, immunoblot, invasion/migration assays, immunohistochemistry in primary OSCC specimens","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined cellular phenotype and pathway placement, single lab","pmids":["30129678"],"is_preprint":false},{"year":2020,"finding":"Migfilin is a pivotal positive regulator of platelet αIIbβ3 outside-in signaling; migfilin-null mice show doubled tail-bleeding time and prolonged thrombosis; migfilin-/- platelets have defective thrombus formation, aggregation, and dense-granule secretion; mechanistically, migfilin hampers re-association of filamin A with the beta3 subunit of αIIbβ3 during outside-in signaling; a cell-permeable migfilin peptide harboring the filamin A-binding sequence rescues the defective function.","method":"Migfilin knockout mice, tail-bleeding assay, FeCl3-induced thrombosis model, platelet function assays, phosphorylation analysis of signaling molecules, cell-permeable peptide rescue, Co-IP (filamin A–beta3 interaction)","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple in vivo and in vitro readouts, mechanistic rescue with peptide, Co-IP validation","pmids":["33131250"],"is_preprint":false},{"year":2011,"finding":"Loss of migfilin expression in mice permits normal development, postnatal aging, and normal integrin expression and activation in fibroblasts and keratinocytes; migration velocity of keratinocytes was slightly but significantly reduced, suggesting functional redundancy in vivo.","method":"Migfilin-null mouse generation, developmental analysis, cell spreading/adhesion assays, integrin activation assays, wound scratch migration assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, single lab","pmids":["21224394"],"is_preprint":false},{"year":2015,"finding":"Migfilin silencing in HCC (HepG2) cells upregulates phospho-VASP (Ser157, Ser239), Fascin-1, and Rho-kinase-1, promoting actin polymerization; decreases phospho-Akt, upregulates free and phospho-beta-catenin, induces proliferation; and upregulates ERK, increasing cell adhesion while reducing invasiveness.","method":"siRNA knockdown, western blot (signaling pathway analysis), invasion assay, cell adhesion assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with pathway analysis, multiple readouts, single lab","pmids":["25773778"],"is_preprint":false},{"year":2017,"finding":"VASP silencing in MDA-MB-231 breast cancer cells downregulates migfilin, beta-catenin, and urokinase-plasminogen activator (uPA) in 2D and 3D culture, and impairs tumor spheroid invasion; placing migfilin downstream of VASP in invasion-related signaling.","method":"siRNA knockdown of VASP, 3D collagen gel invasion assays, western blot, atomic force microscopy","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined 3D invasion phenotype and pathway placement, single lab","pmids":["28209486"],"is_preprint":false}],"current_model":"FBLIM1/migfilin is a focal adhesion scaffold protein that connects cell-matrix (and cell-cell) adhesion structures to the actin cytoskeleton by binding kindlin (via its C-terminal LIM domains), filamin (via its N-terminal domain), Mig-2/kindlin-2, and VASP (via its proline-rich domain); it acts as a molecular switch that displaces filamin from integrin beta cytoplasmic tails to relieve filamin-mediated inhibition of integrin activation, thereby promoting talin binding and integrin activation, and it also activates Src kinase to suppress anoikis, modulates ERK1/2-RANKL signaling to control bone remodeling, regulates platelet αIIbβ3 outside-in signaling by controlling filamin A–beta3 re-association, and shuttles to the nucleus in a calcium-dependent manner to interact with CSX/NKX2-5 and promote cardiomyocyte differentiation."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing migfilin as a focal adhesion scaffold resolved how Mig-2/kindlin-2 connects to the actin cytoskeleton via filamin, defining FBLIM1's tripartite architecture and its role in cell shape modulation.","evidence":"Reciprocal Co-IP, pulldown assays, and siRNA knockdown in cultured cells","pmids":["12679033"],"confidence":"High","gaps":["No structural resolution of binding interfaces","Redundancy with other LIM-domain scaffolds unknown","In vivo requirement not tested"]},{"year":2004,"claim":"Discovery that migfilin shuttles to the nucleus in a calcium-dependent manner and interacts with CSX/NKX2-5 to promote cardiomyocyte differentiation revealed a dual cytoplasmic-nuclear function beyond adhesion scaffolding.","evidence":"Yeast two-hybrid, Co-IP, nuclear export signal mapping, calcium-regulated nuclear translocation, and P19CL6 differentiation assay","pmids":["14757752"],"confidence":"High","gaps":["Transcriptional targets of migfilin–NKX2-5 axis uncharacterized","In vivo cardiac phenotype not demonstrated","Mechanism of calcium-regulated translocation not molecularly defined"]},{"year":2005,"claim":"Demonstration that migfilin localizes to adherens junctions via its LIM domains and is required for junction integrity expanded its role from cell-matrix to cell-cell adhesion.","evidence":"Immunoelectron microscopy, siRNA knockdown, domain deletion, and cell-cell adhesion functional assays in epithelial cells","pmids":["15671069"],"confidence":"High","gaps":["Direct binding partner at adherens junctions (beyond β-catenin) not identified","Cadherin-type specificity unexplored"]},{"year":2006,"claim":"Identification of the migfilin–VASP interaction through a single LPPPPP motif and the EVH1 domain established how migfilin facilitates VASP recruitment to adhesions and promotes cell migration.","evidence":"Co-IP, GST pulldown, point mutagenesis of the LPPPPP motif, siRNA knockdown, and cell migration assays","pmids":["16531412"],"confidence":"High","gaps":["Whether VASP recruitment by migfilin affects actin polymerization dynamics at focal adhesions not directly measured","Specificity among EVH1-domain proteins not tested"]},{"year":2008,"claim":"Structural determination of the migfilin–filamin interface by crystallography and NMR revealed that migfilin and integrin β tails compete for the same CD-face binding surface on IgFLNa21, providing the atomic basis for migfilin as a molecular switch for integrin activation.","evidence":"X-ray crystallography, NMR spectroscopy, and competitive binding assays with purified proteins","pmids":["18829455","19074766"],"confidence":"High","gaps":["How the switch is spatiotemporally regulated inside cells not resolved","Contribution of mechanical force to filamin opening not addressed"]},{"year":2008,"claim":"Showing that kindlin-1 and kindlin-2 both bind migfilin yet that kindlin-1 loss does not affect migfilin localization indicated functional redundancy among kindlins in migfilin recruitment.","evidence":"Co-IP, confocal microscopy, and siRNA knockdown in keratinocytes","pmids":["18528435"],"confidence":"Medium","gaps":["Triple kindlin depletion not performed","Whether kindlin-2 alone is sufficient in all cell types not tested"]},{"year":2009,"claim":"The finding that migfilin directly binds and activates Src kinase to suppress anoikis linked focal adhesion signaling to a cell survival pathway, broadening FBLIM1's role beyond structural scaffolding.","evidence":"Reciprocal Co-IP, direct binding assay, Src kinase activity assay, caspase activation upon migfilin depletion","pmids":["19833732"],"confidence":"High","gaps":["Structural basis of Src activation by migfilin not resolved","Whether Src activation is direct or requires co-factors unknown"]},{"year":2011,"claim":"Migfilin knockout mice developed normally with intact integrin activation, revealing substantial in vivo redundancy, though keratinocyte migration was mildly impaired, implying tissue-specific requirements.","evidence":"Migfilin-null mouse generation, integrin activation assays, wound scratch migration assays","pmids":["21224394"],"confidence":"Medium","gaps":["Identity of compensatory gene(s) not determined","Bone and platelet phenotypes not yet examined in this study"]},{"year":2012,"claim":"FBLIM1 knockout mice exhibited osteopenia with increased osteoclastogenesis driven by ERK1/2-mediated RANKL upregulation, establishing migfilin as a negative regulator of bone resorption signaling.","evidence":"Genetic knockout mouse, bone histomorphometry, BMSC cultures, ERK inhibitor rescue of RANKL levels","pmids":["22556421"],"confidence":"High","gaps":["Molecular mechanism linking migfilin to ERK1/2 activation not defined","Whether the bone phenotype is cell-autonomous to osteoblasts versus osteoclasts not fully resolved"]},{"year":2013,"claim":"FRAP and FRET analyses demonstrated that kindlin binding governs migfilin focal adhesion dynamics, and that without the LIM domains the N-terminal region directs migfilin to stress fibers, establishing a modular targeting code.","evidence":"Kindlin knockdown, FRET/FRAP, domain deletions in cultured cells","pmids":["24165133"],"confidence":"High","gaps":["Whether force-dependent changes in kindlin modulate migfilin residence time not tested","Stoichiometry of migfilin within adhesion complexes unknown"]},{"year":2015,"claim":"A Src–kindlin-2–migfilin positive feedback loop was identified in which Src phosphorylation of kindlin-2 Y193 enhances migfilin binding and focal adhesion recruitment, providing the first phospho-regulatory mechanism for the migfilin–kindlin interaction.","evidence":"In vitro kinase assay, phospho-mutant analysis, Co-IP, cell spreading and migration assays","pmids":["26037143"],"confidence":"Medium","gaps":["In vivo significance of Y193 phosphorylation not tested","Whether other kinases can substitute for Src not examined"]},{"year":2017,"claim":"Identification of recessive FBLIM1 mutations in CRMO patients, coupled with dramatic Fblim1 downregulation in the cmo mouse, established a Mendelian disease link and connected loss of migfilin to sterile bone inflammation.","evidence":"Whole-exome sequencing, enhancer reporter assay, microarray expression profiling in cmo mouse bone marrow macrophages","pmids":["28301468"],"confidence":"Medium","gaps":["Causal rescue of CRMO phenotype by FBLIM1 re-expression not demonstrated","Penetrance and genetic heterogeneity in CRMO families not fully defined","Single study without independent replication"]},{"year":2020,"claim":"Migfilin-null mice displayed prolonged bleeding and defective thrombus formation due to impaired αIIbβ3 outside-in signaling; a cell-permeable migfilin peptide rescued the defect by preventing filamin A–β3 re-association, providing direct in vivo proof that the filamin-displacement mechanism operates in hemostasis.","evidence":"Migfilin KO mice, tail-bleeding assay, FeCl3 thrombosis model, platelet aggregation and dense-granule secretion assays, cell-permeable peptide rescue, Co-IP","pmids":["33131250"],"confidence":"High","gaps":["Whether migfilin peptide has therapeutic potential in thrombotic disease not addressed","Role of migfilin in other platelet integrins not examined"]},{"year":null,"claim":"The molecular basis by which migfilin toggles between focal adhesion, adherens junction, and nuclear functions — and how these distinct pools are coordinated in vivo — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length migfilin","Post-translational modification landscape beyond Y193 on kindlin-2 largely unexplored","Compensatory genes masking KO phenotypes not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,4,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7,8,18]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,9,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,8,14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,6,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,15]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[18]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7]}],"complexes":["Integrin-kindlin-migfilin-filamin complex","Adherens junction complex"],"partners":["FLNA","FLNB","FLNC","FERMT1","FERMT2","VASP","SRC","NKX2-5"],"other_free_text":[]},"mechanistic_narrative":"FBLIM1 (migfilin) is a multidomain focal adhesion scaffold protein that coordinates integrin activation, cytoskeletal organization, cell adhesion, and signal transduction across cell-matrix and cell-cell junctions. Its N-terminal domain competitively displaces filamin from integrin β cytoplasmic tails at a shared binding surface on IgFLNa21, relieving filamin-mediated inhibition and enabling talin-dependent integrin activation, a mechanism critical for platelet αIIbβ3 outside-in signaling and thrombus formation [PMID:19074766, PMID:33131250]. The C-terminal LIM domains mediate recruitment to focal adhesions via kindlin-1/2 interaction and to adherens junctions via β-catenin association, while a central proline-rich domain engages VASP to regulate cell migration; migfilin also activates Src kinase to suppress anoikis, modulates ERK1/2-RANKL signaling to control bone remodeling, and shuttles to the nucleus in a calcium-dependent manner to interact with CSX/NKX2-5 and promote cardiomyocyte differentiation [PMID:14757752, PMID:16531412, PMID:15671069, PMID:19833732, PMID:22556421]. Recessive FBLIM1 mutations underlie chronic recurrent multifocal osteomyelitis (CRMO), and the cmo mouse model exhibits dramatic downregulation of the Fblim1 ortholog in bone marrow macrophages [PMID:28301468]."},"prefetch_data":{"uniprot":{"accession":"Q8WUP2","full_name":"Filamin-binding LIM protein 1","aliases":["Migfilin","Mitogen-inducible 2-interacting protein","MIG2-interacting protein"],"length_aa":373,"mass_kda":40.7,"function":"Serves as an anchoring site for cell-ECM adhesion proteins and filamin-containing actin filaments. Is implicated in cell shape modulation (spreading) and motility. May participate in the regulation of filamin-mediated cross-linking and stabilization of actin filaments. May also regulate the assembly of filamin-containing signaling complexes that control actin assembly. Promotes dissociation of FLNA from ITGB3 and ITGB7. Promotes activation of integrins and regulates integrin-mediated cell-cell adhesion","subcellular_location":"Cell junction, focal adhesion; Cytoplasm, cytoskeleton, stress fiber","url":"https://www.uniprot.org/uniprotkb/Q8WUP2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/FBLIM1","classification":"Common Essential","n_dependent_lines":621,"n_total_lines":1208,"dependency_fraction":0.5140728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBLIM1","total_profiled":1310},"omim":[{"mim_id":"607747","title":"FILAMIN-BINDING LIM PROTEIN 1; FBLIM1","url":"https://www.omim.org/entry/607747"},{"mim_id":"259680","title":"CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS 3; CRMO3","url":"https://www.omim.org/entry/259680"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cell Junctions","reliability":"Enhanced"},{"location":"Focal adhesion sites","reliability":"Enhanced"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":444.4}],"url":"https://www.proteinatlas.org/search/FBLIM1"},"hgnc":{"alias_symbol":["FBLP-1","CAL","migfilin"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUP2","domains":[{"cath_id":"2.10.110.10","chopping":"182-240","consensus_level":"medium","plddt":86.5534,"start":182,"end":240},{"cath_id":"2.10.110.10","chopping":"249-300","consensus_level":"medium","plddt":86.9621,"start":249,"end":300},{"cath_id":"2.10.110.10","chopping":"302-373","consensus_level":"medium","plddt":81.5185,"start":302,"end":373}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUP2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUP2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUP2-F1-predicted_aligned_error_v6.png","plddt_mean":66.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBLIM1","jax_strain_url":"https://www.jax.org/strain/search?query=FBLIM1"},"sequence":{"accession":"Q8WUP2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUP2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUP2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUP2"}},"corpus_meta":[{"pmid":"20959606","id":"PMC_20959606","title":"CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20959606","citation_count":617,"is_preprint":false},{"pmid":"20522708","id":"PMC_20522708","title":"Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20522708","citation_count":459,"is_preprint":false},{"pmid":"21803855","id":"PMC_21803855","title":"The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/21543871","citation_count":12,"is_preprint":false},{"pmid":"810266","id":"PMC_810266","title":"Isolation and characterization of cal allergens.","date":"1975","source":"Clinical allergy","url":"https://pubmed.ncbi.nlm.nih.gov/810266","citation_count":12,"is_preprint":false},{"pmid":"32650789","id":"PMC_32650789","title":"High prevalence of rare FBLIM1 gene variants in an Italian cohort of patients with Chronic Non-bacterial Osteomyelitis (CNO).","date":"2020","source":"Pediatric rheumatology online journal","url":"https://pubmed.ncbi.nlm.nih.gov/32650789","citation_count":11,"is_preprint":false},{"pmid":"23645746","id":"PMC_23645746","title":"Mitogen-inducible Gene-2 (MIG2) and migfilin expression is reduced in samples of human breast cancer.","date":"2013","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23645746","citation_count":11,"is_preprint":false},{"pmid":"19263457","id":"PMC_19263457","title":"Nm23-H1 promotes adhesion of CAL 27 cells in vitro.","date":"2009","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/19263457","citation_count":11,"is_preprint":false},{"pmid":"29472314","id":"PMC_29472314","title":"Cysteine modifiers suggest an allosteric inhibitory site on the CAL PDZ domain.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/29472314","citation_count":11,"is_preprint":false},{"pmid":"24648926","id":"PMC_24648926","title":"In vitro effect of molluscan hemocyanins on CAL-29 and T-24 bladder cancer cell lines.","date":"2012","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/24648926","citation_count":11,"is_preprint":false},{"pmid":"28972668","id":"PMC_28972668","title":"Wenxin Keli diminishes Ca2+ overload induced by hypoxia/reoxygenation in cardiomyocytes through inhibiting INaL and ICaL.","date":"2017","source":"Pacing and clinical electrophysiology : PACE","url":"https://pubmed.ncbi.nlm.nih.gov/28972668","citation_count":11,"is_preprint":false},{"pmid":"26854885","id":"PMC_26854885","title":"The immunomodulatory activities of pullulan and its derivatives in human pDC-like CAL-1 cell line.","date":"2016","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/26854885","citation_count":11,"is_preprint":false},{"pmid":"37372064","id":"PMC_37372064","title":"Compatible Consortium of Endophytic Bacillus halotolerans Strains Cal.l.30 and Cal.f.4 Promotes Plant Growth and Induces Systemic Resistance against Botrytis cinerea.","date":"2023","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37372064","citation_count":11,"is_preprint":false},{"pmid":"1650708","id":"PMC_1650708","title":"Brief exposure to the G-protein activator NaF/AlCl3 induces prolonged enhancement of synaptic transmission in area CAl of rat hippocampal slices.","date":"1991","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/1650708","citation_count":11,"is_preprint":false},{"pmid":"33131250","id":"PMC_33131250","title":"Migfilin supports hemostasis and thrombosis through regulating platelet αIIbβ3 outside-in signaling.","date":"2020","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/33131250","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50056,"output_tokens":5177,"usd":0.113911},"stage2":{"model":"claude-opus-4-6","input_tokens":8734,"output_tokens":3285,"usd":0.188693},"total_usd":0.302604,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Migfilin (FBLIM1) localizes to cell-matrix adhesions, interacts with Mig-2 (kindlin-2 homolog UNC-112) through its C-terminal domain and with filamin through its N-terminal domain, thereby functioning as a scaffold linking cell-matrix adhesions to the actin cytoskeleton and regulating cell shape modulation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, siRNA knockdown, loss-of-function phenotypic analysis (cell shape modulation defects)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, and siRNA KD with defined cellular phenotype in foundational paper with >300 citations\",\n      \"pmids\": [\"12679033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The N-terminal portion of migfilin binds all three human filamins (FLNa, FLNb, FLNc), preferentially to IgFLNa21 and more weakly to IgFLNa19 and IgFLNa22 via the CD face of the IgFLN beta-sandwich. The migfilin-filamin binding site (Pro5–Pro19) overlaps with the integrin beta tail binding site on IgFLNa21, allowing migfilin and integrin beta tails to compete for the same filamin binding surface.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, protein-protein interaction competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure and NMR with functional validation of competitive binding mechanism\",\n      \"pmids\": [\"18829455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Migfilin structurally interacts with filamin at the same region where integrin beta cytoplasmic tails bind, and this interaction dissociates filamin from integrin, promoting talin/integrin binding and integrin activation; migfilin thus acts as a molecular switch between filamin-mediated inhibition and talin-mediated activation of integrins.\",\n      \"method\": \"NMR structural analysis, pulldown assays, integrin activation functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and functional reconstitution with mechanistic validation\",\n      \"pmids\": [\"19074766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Migfilin contains an N-terminal filamin-binding domain, a central proline-rich domain, and three C-terminal LIM domains; it is recruited to cell-matrix contacts upon adhesion, colocalizes with beta-catenin at cell-cell junctions, shuttles from cytoplasm to nucleus in a process regulated by RNA splicing and calcium signaling, and interacts with VASP and the cardiac transcription factor CSX/NKX2-5.\",\n      \"method\": \"Biochemical interaction studies, live-cell imaging, domain deletion analysis, yeast two-hybrid\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — review synthesizing primary data from multiple binding partner identification studies\",\n      \"pmids\": [\"15701922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Migfilin interacts with vasodilator-stimulated phosphoprotein (VASP) via the VASP EVH1 domain and a single LPPPPP site in the migfilin proline-rich domain; this interaction facilitates VASP localization to cell-matrix adhesions and is required for migfilin-regulated cell migration.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, domain mutagenesis, siRNA knockdown, cell migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis of interaction site, VASP KD rescue experiment, cellular functional readout\",\n      \"pmids\": [\"16531412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Migfilin (Cal/FBLIM1) interacts with the cardiac transcription factor CSX/NKX2-5 via its LIM domains and the NKX2-5 homeodomain; migfilin possesses transcription-promoting activity, contains a functional nuclear export signal, shuttles to the nucleus in response to calcium, and promotes myocardial cell differentiation when accumulated in the nucleus.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, in vitro binding, nuclear export signal analysis, calcium-regulated nuclear translocation assay, P19CL6 differentiation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, domain mapping, and functional differentiation assay\",\n      \"pmids\": [\"14757752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Migfilin is recruited to cell-cell junctions (adherens junctions) in response to cadherin-mediated adhesion; the C-terminal LIM domains mediate this localization; migfilin associates with beta-catenin but not desmosomes at cell-cell junctions; siRNA-mediated depletion of migfilin compromises adherens junction organization and weakens cell-cell association.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy, siRNA knockdown, domain deletion analysis, cell-cell adhesion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence via siRNA KD and domain mapping\",\n      \"pmids\": [\"15671069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Migfilin directly interacts with Src kinase, with the migfilin binding surface overlapping the inhibitory intramolecular interaction sites in Src; this interaction activates Src, leading to suppression of anoikis; loss of cell-ECM adhesion reduces migfilin levels and induces apoptosis, and overexpression of migfilin desensitizes cells to detachment-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, overexpression/depletion experiments, apoptosis assays (caspase activation), Src kinase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, Src activation assay, gain- and loss-of-function with defined apoptotic phenotype\",\n      \"pmids\": [\"19833732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Migfilin displaces filamin from beta1 and beta3 integrins and promotes integrin activation in endothelial cells and neutrophils; filamin acts broadly as an inhibitor of integrin activation and migfilin overcomes this inhibition; migfilin depletion impairs spreading and migration of endothelial cells.\",\n      \"method\": \"Flow cytometry (integrin activation), siRNA knockdown, spreading and migration assays in primary vascular cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional integrin activation assay with KD in primary cells, moderate evidence from single lab\",\n      \"pmids\": [\"22043318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR spectroscopy demonstrates that filamin autoinhibition of integrin-binding repeats 19 and 21 can be relieved by integrin or by migfilin via a multisite binding mechanism, with repeats 19 and 21 simultaneously engaging ligands, suggesting filamin is mechanically stretched by migfilin/integrin interaction.\",\n      \"method\": \"NMR spectroscopy, binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural analysis, single lab\",\n      \"pmids\": [\"21524097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kindlin-1 and kindlin-2 interact with migfilin (FBLIM1) and colocalize at focal adhesions in keratinocytes; loss of kindlin-1 does not affect FBLIM1 gene expression or migfilin protein localization, indicating migfilin can function independently of kindlin-1.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, siRNA knockdown, immunostaining\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and imaging with functional independence established by KD\",\n      \"pmids\": [\"18528435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic inactivation of FBLIM1 (encoding FBLP-1/migfilin) in mice causes osteopenic phenotype; loss of FBLP-1 impairs BMSC adhesion, migration, growth, and survival; reduces osteoblast progenitors and differentiation; dramatically increases osteoclast differentiation; markedly elevates RANKL in null BMSCs via ERK1/2 hyperactivation; ERK1/2 inhibition suppresses the RANKL increase.\",\n      \"method\": \"Genetic knockout (mouse), primary cell culture assays (adhesion, migration, proliferation, differentiation), in vivo bone histomorphometry, western blot (RANKL, pERK), pharmacological ERK inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal cellular and in vivo phenotypic readouts plus pathway placement via ERK inhibition\",\n      \"pmids\": [\"22556421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Migfilin promotes migration and invasion in glioma cells by positively modulating EGFR expression and activity; migfilin-mediated migration and invasion depend on EGFR-induced PLC-gamma and STAT3 signaling pathways.\",\n      \"method\": \"Immunohistochemistry, siRNA knockdown, migration/invasion assays, western blot (EGFR, PLC-gamma, STAT3 phosphorylation)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined pathway placement, single lab\",\n      \"pmids\": [\"22843679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Migfilin inhibits esophageal cancer cell motility by promoting GSK-3beta-mediated phosphorylation and proteasomal degradation of beta-catenin; migfilin reinforces the association between beta-catenin and GSK-3beta; overexpression of beta-catenin or inhibition of GSK-3beta reverses migfilin-mediated suppression of invasion.\",\n      \"method\": \"Overexpression, siRNA knockdown, beta-catenin reporter assay, co-IP (migfilin–beta-catenin–GSK-3beta complex), proteasome inhibitor rescue, invasion assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of complex, mechanistic rescue experiments with inhibitors and mutants\",\n      \"pmids\": [\"22246236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kindlin-1 and kindlin-2 bind the C-terminal tandem LIM domains of migfilin; this interaction drives migfilin FA recruitment, localization, and mobility; FRAP and FRET analyses show kindlin depletion alters migfilin dynamics; when the C-terminal LIM region is deleted, the N-terminal filamin-binding region directs migfilin to actin stress fibers instead.\",\n      \"method\": \"Kindlin knockdown, biochemical pulldown, fluorescence microscopy, FRET, FRAP, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical + live-cell imaging dynamics) establishing interaction and functional consequence\",\n      \"pmids\": [\"24165133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Src phosphorylates kindlin-2 at Y193, which enhances Src kinase activity; kindlin-2 Y193 phosphorylation is required for migfilin binding to kindlin-2 and the recruitment of migfilin to focal adhesions; this constitutes a positive feedback loop among Src, kindlin-2, and migfilin.\",\n      \"method\": \"In vitro kinase assay, phospho-specific mutant analysis, Co-IP, immunofluorescence, cell spreading and migration assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase assay plus Co-IP plus functional cell assay, single lab\",\n      \"pmids\": [\"26037143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Recessive mutations in the filamin-binding domain of FBLIM1, as well as regulatory variants ablating an enhancer, underlie chronic recurrent multifocal osteomyelitis (CRMO); the Fblim1 ortholog is the most differentially expressed gene (>20-fold downregulated) in bone marrow macrophages of the cmo mouse model.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, microarray expression analysis of cmo mouse BMMs, enhancer reporter assay in SaOS2 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic evidence plus reporter assay, single lab\",\n      \"pmids\": [\"28301468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBLIM1 knockdown in OSCC cells attenuates proliferation, migration, and invasiveness; FBLIM1 expression correlates with EGFR activity; clopidogrel treatment downregulates both EGFR and FBLIM1, phenocopying the KD effect, placing FBLIM1 upstream or co-regulatory with EGFR signaling in oral cancer.\",\n      \"method\": \"siRNA knockdown, clopidogrel pharmacological inhibition, qRT-PCR, immunoblot, invasion/migration assays, immunohistochemistry in primary OSCC specimens\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"30129678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Migfilin is a pivotal positive regulator of platelet αIIbβ3 outside-in signaling; migfilin-null mice show doubled tail-bleeding time and prolonged thrombosis; migfilin-/- platelets have defective thrombus formation, aggregation, and dense-granule secretion; mechanistically, migfilin hampers re-association of filamin A with the beta3 subunit of αIIbβ3 during outside-in signaling; a cell-permeable migfilin peptide harboring the filamin A-binding sequence rescues the defective function.\",\n      \"method\": \"Migfilin knockout mice, tail-bleeding assay, FeCl3-induced thrombosis model, platelet function assays, phosphorylation analysis of signaling molecules, cell-permeable peptide rescue, Co-IP (filamin A–beta3 interaction)\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple in vivo and in vitro readouts, mechanistic rescue with peptide, Co-IP validation\",\n      \"pmids\": [\"33131250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of migfilin expression in mice permits normal development, postnatal aging, and normal integrin expression and activation in fibroblasts and keratinocytes; migration velocity of keratinocytes was slightly but significantly reduced, suggesting functional redundancy in vivo.\",\n      \"method\": \"Migfilin-null mouse generation, developmental analysis, cell spreading/adhesion assays, integrin activation assays, wound scratch migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, single lab\",\n      \"pmids\": [\"21224394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Migfilin silencing in HCC (HepG2) cells upregulates phospho-VASP (Ser157, Ser239), Fascin-1, and Rho-kinase-1, promoting actin polymerization; decreases phospho-Akt, upregulates free and phospho-beta-catenin, induces proliferation; and upregulates ERK, increasing cell adhesion while reducing invasiveness.\",\n      \"method\": \"siRNA knockdown, western blot (signaling pathway analysis), invasion assay, cell adhesion assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with pathway analysis, multiple readouts, single lab\",\n      \"pmids\": [\"25773778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VASP silencing in MDA-MB-231 breast cancer cells downregulates migfilin, beta-catenin, and urokinase-plasminogen activator (uPA) in 2D and 3D culture, and impairs tumor spheroid invasion; placing migfilin downstream of VASP in invasion-related signaling.\",\n      \"method\": \"siRNA knockdown of VASP, 3D collagen gel invasion assays, western blot, atomic force microscopy\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined 3D invasion phenotype and pathway placement, single lab\",\n      \"pmids\": [\"28209486\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBLIM1/migfilin is a focal adhesion scaffold protein that connects cell-matrix (and cell-cell) adhesion structures to the actin cytoskeleton by binding kindlin (via its C-terminal LIM domains), filamin (via its N-terminal domain), Mig-2/kindlin-2, and VASP (via its proline-rich domain); it acts as a molecular switch that displaces filamin from integrin beta cytoplasmic tails to relieve filamin-mediated inhibition of integrin activation, thereby promoting talin binding and integrin activation, and it also activates Src kinase to suppress anoikis, modulates ERK1/2-RANKL signaling to control bone remodeling, regulates platelet αIIbβ3 outside-in signaling by controlling filamin A–beta3 re-association, and shuttles to the nucleus in a calcium-dependent manner to interact with CSX/NKX2-5 and promote cardiomyocyte differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBLIM1 (migfilin) is a multidomain focal adhesion scaffold protein that coordinates integrin activation, cytoskeletal organization, cell adhesion, and signal transduction across cell-matrix and cell-cell junctions. Its N-terminal domain competitively displaces filamin from integrin β cytoplasmic tails at a shared binding surface on IgFLNa21, relieving filamin-mediated inhibition and enabling talin-dependent integrin activation, a mechanism critical for platelet αIIbβ3 outside-in signaling and thrombus formation [PMID:19074766, PMID:33131250]. The C-terminal LIM domains mediate recruitment to focal adhesions via kindlin-1/2 interaction and to adherens junctions via β-catenin association, while a central proline-rich domain engages VASP to regulate cell migration; migfilin also activates Src kinase to suppress anoikis, modulates ERK1/2-RANKL signaling to control bone remodeling, and shuttles to the nucleus in a calcium-dependent manner to interact with CSX/NKX2-5 and promote cardiomyocyte differentiation [PMID:14757752, PMID:16531412, PMID:15671069, PMID:19833732, PMID:22556421]. Recessive FBLIM1 mutations underlie chronic recurrent multifocal osteomyelitis (CRMO), and the cmo mouse model exhibits dramatic downregulation of the Fblim1 ortholog in bone marrow macrophages [PMID:28301468].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing migfilin as a focal adhesion scaffold resolved how Mig-2/kindlin-2 connects to the actin cytoskeleton via filamin, defining FBLIM1's tripartite architecture and its role in cell shape modulation.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldown assays, and siRNA knockdown in cultured cells\",\n      \"pmids\": [\"12679033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural resolution of binding interfaces\", \"Redundancy with other LIM-domain scaffolds unknown\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that migfilin shuttles to the nucleus in a calcium-dependent manner and interacts with CSX/NKX2-5 to promote cardiomyocyte differentiation revealed a dual cytoplasmic-nuclear function beyond adhesion scaffolding.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, nuclear export signal mapping, calcium-regulated nuclear translocation, and P19CL6 differentiation assay\",\n      \"pmids\": [\"14757752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets of migfilin–NKX2-5 axis uncharacterized\", \"In vivo cardiac phenotype not demonstrated\", \"Mechanism of calcium-regulated translocation not molecularly defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that migfilin localizes to adherens junctions via its LIM domains and is required for junction integrity expanded its role from cell-matrix to cell-cell adhesion.\",\n      \"evidence\": \"Immunoelectron microscopy, siRNA knockdown, domain deletion, and cell-cell adhesion functional assays in epithelial cells\",\n      \"pmids\": [\"15671069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner at adherens junctions (beyond β-catenin) not identified\", \"Cadherin-type specificity unexplored\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of the migfilin–VASP interaction through a single LPPPPP motif and the EVH1 domain established how migfilin facilitates VASP recruitment to adhesions and promotes cell migration.\",\n      \"evidence\": \"Co-IP, GST pulldown, point mutagenesis of the LPPPPP motif, siRNA knockdown, and cell migration assays\",\n      \"pmids\": [\"16531412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VASP recruitment by migfilin affects actin polymerization dynamics at focal adhesions not directly measured\", \"Specificity among EVH1-domain proteins not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Structural determination of the migfilin–filamin interface by crystallography and NMR revealed that migfilin and integrin β tails compete for the same CD-face binding surface on IgFLNa21, providing the atomic basis for migfilin as a molecular switch for integrin activation.\",\n      \"evidence\": \"X-ray crystallography, NMR spectroscopy, and competitive binding assays with purified proteins\",\n      \"pmids\": [\"18829455\", \"19074766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the switch is spatiotemporally regulated inside cells not resolved\", \"Contribution of mechanical force to filamin opening not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that kindlin-1 and kindlin-2 both bind migfilin yet that kindlin-1 loss does not affect migfilin localization indicated functional redundancy among kindlins in migfilin recruitment.\",\n      \"evidence\": \"Co-IP, confocal microscopy, and siRNA knockdown in keratinocytes\",\n      \"pmids\": [\"18528435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Triple kindlin depletion not performed\", \"Whether kindlin-2 alone is sufficient in all cell types not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The finding that migfilin directly binds and activates Src kinase to suppress anoikis linked focal adhesion signaling to a cell survival pathway, broadening FBLIM1's role beyond structural scaffolding.\",\n      \"evidence\": \"Reciprocal Co-IP, direct binding assay, Src kinase activity assay, caspase activation upon migfilin depletion\",\n      \"pmids\": [\"19833732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Src activation by migfilin not resolved\", \"Whether Src activation is direct or requires co-factors unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Migfilin knockout mice developed normally with intact integrin activation, revealing substantial in vivo redundancy, though keratinocyte migration was mildly impaired, implying tissue-specific requirements.\",\n      \"evidence\": \"Migfilin-null mouse generation, integrin activation assays, wound scratch migration assays\",\n      \"pmids\": [\"21224394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of compensatory gene(s) not determined\", \"Bone and platelet phenotypes not yet examined in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"FBLIM1 knockout mice exhibited osteopenia with increased osteoclastogenesis driven by ERK1/2-mediated RANKL upregulation, establishing migfilin as a negative regulator of bone resorption signaling.\",\n      \"evidence\": \"Genetic knockout mouse, bone histomorphometry, BMSC cultures, ERK inhibitor rescue of RANKL levels\",\n      \"pmids\": [\"22556421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking migfilin to ERK1/2 activation not defined\", \"Whether the bone phenotype is cell-autonomous to osteoblasts versus osteoclasts not fully resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"FRAP and FRET analyses demonstrated that kindlin binding governs migfilin focal adhesion dynamics, and that without the LIM domains the N-terminal region directs migfilin to stress fibers, establishing a modular targeting code.\",\n      \"evidence\": \"Kindlin knockdown, FRET/FRAP, domain deletions in cultured cells\",\n      \"pmids\": [\"24165133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether force-dependent changes in kindlin modulate migfilin residence time not tested\", \"Stoichiometry of migfilin within adhesion complexes unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A Src–kindlin-2–migfilin positive feedback loop was identified in which Src phosphorylation of kindlin-2 Y193 enhances migfilin binding and focal adhesion recruitment, providing the first phospho-regulatory mechanism for the migfilin–kindlin interaction.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mutant analysis, Co-IP, cell spreading and migration assays\",\n      \"pmids\": [\"26037143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo significance of Y193 phosphorylation not tested\", \"Whether other kinases can substitute for Src not examined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of recessive FBLIM1 mutations in CRMO patients, coupled with dramatic Fblim1 downregulation in the cmo mouse, established a Mendelian disease link and connected loss of migfilin to sterile bone inflammation.\",\n      \"evidence\": \"Whole-exome sequencing, enhancer reporter assay, microarray expression profiling in cmo mouse bone marrow macrophages\",\n      \"pmids\": [\"28301468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal rescue of CRMO phenotype by FBLIM1 re-expression not demonstrated\", \"Penetrance and genetic heterogeneity in CRMO families not fully defined\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Migfilin-null mice displayed prolonged bleeding and defective thrombus formation due to impaired αIIbβ3 outside-in signaling; a cell-permeable migfilin peptide rescued the defect by preventing filamin A–β3 re-association, providing direct in vivo proof that the filamin-displacement mechanism operates in hemostasis.\",\n      \"evidence\": \"Migfilin KO mice, tail-bleeding assay, FeCl3 thrombosis model, platelet aggregation and dense-granule secretion assays, cell-permeable peptide rescue, Co-IP\",\n      \"pmids\": [\"33131250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether migfilin peptide has therapeutic potential in thrombotic disease not addressed\", \"Role of migfilin in other platelet integrins not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis by which migfilin toggles between focal adhesion, adherens junction, and nuclear functions — and how these distinct pools are coordinated in vivo — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length migfilin\", \"Post-translational modification landscape beyond Y193 on kindlin-2 largely unexplored\", \"Compensatory genes masking KO phenotypes not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 4, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7, 8, 18]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 9, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 8, 14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 6, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 15]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"Integrin-kindlin-migfilin-filamin complex\",\n      \"Adherens junction complex\"\n    ],\n    \"partners\": [\n      \"FLNA\",\n      \"FLNB\",\n      \"FLNC\",\n      \"FERMT1\",\n      \"FERMT2\",\n      \"VASP\",\n      \"SRC\",\n      \"NKX2-5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}