{"gene":"FBLIM1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"Migfilin localizes to cell-matrix adhesions, associates with actin filaments, and is essential for cell shape modulation. Migfilin interacts with Mig-2 (kindlin/UNC-112 homolog) through its C-terminal domain and with filamin through its N-terminal domain. Mig-2 recruits migfilin to cell-matrix adhesions, while the interaction with filamin mediates migfilin's association with actin filaments.","method":"Co-immunoprecipitation, pulldown assays, siRNA knockdown, dominant-negative overexpression, fluorescence microscopy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional knockdown with defined cellular phenotype, multiple orthogonal methods, independently replicated in subsequent studies","pmids":["12679033"],"is_preprint":false},{"year":2005,"finding":"Migfilin localizes to cell-cell junctions in epithelial and endothelial cells in response to cadherin-mediated adhesion, forming detergent-resistant clusters associated with actin bundles. The C-terminal LIM domains mediate localization to cell-cell junctions. siRNA depletion of migfilin compromised adherens junction organization and weakened cell-cell association. Immunoelectron microscopy showed migfilin associates with beta-catenin (not desmosomes) at cell-cell junctions.","method":"siRNA knockdown, immunoelectron microscopy, confocal microscopy, detergent fractionation, domain deletion mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (immunoEM, FACS, KD with phenotype, domain mapping), single lab","pmids":["15671069"],"is_preprint":false},{"year":2006,"finding":"Migfilin interacts with VASP through the VASP EVH1 domain and a single LPPPPP site (L104) in migfilin's proline-rich domain. Migfilin facilitates VASP localization to cell-matrix adhesions. Both loss and overexpression of migfilin reduce cell migration (biphasic regulation). VASP-binding defective migfilin mutants abolish migfilin-mediated regulation of cell migration.","method":"Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, migration assay, fluorescence colocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — binding domain mapped by mutagenesis, functional KD with phenotype, multiple orthogonal methods, single lab","pmids":["16531412"],"is_preprint":false},{"year":2008,"finding":"X-ray crystallography and NMR revealed the structural basis of migfilin binding to filamin. The filamin-binding site in migfilin is localized between Pro5 and Pro19, binding to the CD face of IgFLNa21 beta-sandwich. Migfilin binds all three human filamins (FLNa, -b, -c) with preference for IgFLNa21, and also more weakly to IgFLNa19 and IgFLNa22. Migfilin and integrin beta tails compete for the same binding site on IgFLNa21, suggesting migfilin can displace integrin from filamin.","method":"X-ray crystallography, NMR spectroscopy, protein-protein interaction assays, competition binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus NMR plus biochemical binding assays, multiple orthogonal methods, single lab","pmids":["18829455"],"is_preprint":false},{"year":2008,"finding":"Migfilin structurally interacts with the same region in filamin where integrin beta cytoplasmic tails bind, and this interaction dissociates filamin from integrin beta tails, thereby promoting talin-integrin interaction and integrin activation. Migfilin thus acts as a molecular switch to disconnect filamin from integrin for regulating integrin activation.","method":"Structural studies (NMR/biochemical), competition binding assays, cell-based integrin activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural and biochemical reconstitution, functional cell-based validation, corroborated by independent studies (PMID:18829455, 22043318)","pmids":["19074766"],"is_preprint":false},{"year":2008,"finding":"Kindlin-1 interacts with both kindlin-2 and migfilin; the three proteins co-immunoprecipitate and colocalize at focal adhesions in keratinocytes. Loss of kindlin-1 expression does not affect KIND2 or FBLIM1 gene expression or kindlin-2/migfilin protein localization, indicating kindlin-1 can function independently of kindlin-2 and migfilin.","method":"Co-immunoprecipitation, confocal microscopy, siRNA knockdown, immunohistochemistry","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP and colocalization, single lab, limited mechanistic follow-up","pmids":["18528435"],"is_preprint":false},{"year":2009,"finding":"Migfilin directly interacts with Src kinase; the migfilin binding surface overlaps with the inhibitory intramolecular interaction sites in Src, resulting in Src activation upon migfilin binding. Loss of cell-ECM adhesion reduces migfilin levels and induces apoptosis. Migfilin overexpression desensitizes cells to detachment-induced apoptosis; migfilin depletion promotes apoptosis despite cell-ECM adhesion.","method":"Co-immunoprecipitation, pulldown assays, siRNA knockdown, overexpression, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, functional KD/OE with defined apoptosis phenotype, mechanistic link to Src activation mapped, single lab","pmids":["19833732"],"is_preprint":false},{"year":2011,"finding":"NMR spectroscopy showed that filamin autoinhibition of repeats 19 and 21 can be relieved by migfilin (or integrin), and repeats 19 and 21 can simultaneously engage ligands, suggesting migfilin mechanically stretches filamin via multisite binding to regulate cytoskeleton and integrin-mediated cell adhesion.","method":"NMR spectroscopy, binding assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous NMR method but single lab, no cellular functional follow-up reported in abstract","pmids":["21524097"],"is_preprint":false},{"year":2011,"finding":"Flow cytometry demonstrated that filamin inhibits β1 and αIIbβ3 integrin activation, and migfilin can overcome this inhibitory effect. Migfilin can activate β1, β2, and β3 integrins in endothelial cells and neutrophils. Migfilin depletion impairs spreading and migration of endothelial cells.","method":"Flow cytometry, siRNA knockdown, cell spreading and migration assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD in primary vascular cells, flow cytometry for integrin activation, multiple integrin subtypes tested, single lab","pmids":["22043318"],"is_preprint":false},{"year":2011,"finding":"In migfilin-null mice generated by genetic inactivation, development and postnatal aging were normal. Fibroblasts and keratinocytes from migfilin-null mice displayed normal spreading, adhesion, integrin expression, and integrin activation. Migration velocity of null embryonic fibroblasts was normal, but migfilin-null keratinocyte migration was slightly reduced in wound scratch assays. This indicates migfilin roles are functionally redundant during mouse development and tissue homeostasis.","method":"Genetic knockout mouse, cell spreading/adhesion assays, flow cytometry for integrin activation, wound scratch migration assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — constitutive knockout mouse with multiple orthogonal readouts; findings are largely negative for major developmental phenotype, single lab","pmids":["21224394"],"is_preprint":false},{"year":2012,"finding":"Genetic inactivation of FBLIM1 in mice caused severe osteopenic phenotype. FBLP-1 null bone marrow stromal cells (BMSCs) showed reduced ECM adhesion and migration. Loss of FBLP-1 impaired BMSC growth and survival, decreased osteoblast progenitor numbers and differentiation, and dramatically increased osteoclast differentiation in vivo. RANKL levels were markedly elevated in FBLP-1 null BMSCs. Loss of FBLP-1 promoted activating phosphorylation of ERK1/2, and ERK1/2 inhibition suppressed the increase of RANKL. FBLP-1 null bone marrow monocytes differentiated normally into osteoclasts when provided exogenous RANKL.","method":"Genetic knockout mouse, primary cell culture, cell adhesion/migration assays, RANKL ELISA, ERK inhibitor treatment, histology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive knockout mouse with multiple defined cellular and molecular phenotypes, pharmacological rescue, single lab with multiple orthogonal methods","pmids":["22556421"],"is_preprint":false},{"year":2012,"finding":"Migfilin promotes GSK-3β-mediated degradation of β-catenin in esophageal cancer cells. Overexpression of migfilin reduced free β-catenin levels and transcriptional activity; this was reversed by siRNA knockdown of migfilin, a Ser37 phosphorylation-deficient β-catenin mutant, GSK-3β inhibitor (LiCl), or proteasome inhibitor (MG132). Migfilin reinforced the association between β-catenin and GSK-3β.","method":"Overexpression, siRNA knockdown, GSK-3β inhibitor, proteasome inhibitor, co-immunoprecipitation, Western blot","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches, mechanistic pathway mapped, single lab","pmids":["22246236"],"is_preprint":false},{"year":2013,"finding":"Kindlin-1 and kindlin-2 interact with the C-terminal LIM domains of migfilin in vitro and in cells. The C-terminal LIM domains of migfilin dictate FA localization; deletion of this region reveals the N-terminal filamin-binding region drives localization to actin-rich stress fibers. Kindlin knockdown disrupts normal migfilin dynamics (FA recruitment and mobility) as shown by FRAP and FRET assays.","method":"Pulldown assays, fluorescence microscopy, FRET, FRAP, kindlin siRNA knockdown, domain deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (FRAP, FRET, pulldown, KD), domain mapping and functional consequence defined, single lab","pmids":["24165133"],"is_preprint":false},{"year":2015,"finding":"Kindlin-2 phosphorylation by Src at Y193 is involved in Migfilin binding to kindlin-2 and recruitment of Migfilin to focal adhesions. Src phosphorylates kindlin-2 at Y193; reciprocally, this phosphorylation activates and maintains Src kinase activity, forming a positive feedback loop involving Src, kindlin-2, and migfilin.","method":"Co-immunoprecipitation, site-directed mutagenesis, kinase assays, Western blot for phosphorylation, fluorescence microscopy","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation site, functional localization and signaling readouts, single lab","pmids":["26037143"],"is_preprint":false},{"year":2015,"finding":"In a migfilin knockout mouse subjected to transverse aortic constriction (TAC), migfilin-null hearts showed reduced extent of hypertrophic remodeling and maintained cardiac function longer than WT mice. Migfilin translocated into the nucleus of TAC-treated cardiomyocytes. Migfilin KO hearts showed reduced Akt activation during early response to pressure overload.","method":"Knockout mouse model, transverse aortic constriction, echocardiography, immunofluorescence for nuclear translocation, Western blot for Akt phosphorylation","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with defined cardiac phenotype, nuclear translocation shown, signaling pathway identified, single lab","pmids":["25852081"],"is_preprint":false},{"year":2017,"finding":"A homozygous mutation in the filamin-binding domain of FBLIM1 was identified in a CRMO patient. Microarray analysis showed the Fblim1 ortholog is the most differentially expressed gene (downregulated >20-fold) in bone marrow macrophages from the cmo murine CRMO model. An enhancer element flanking FBLIM1 was identified; a regulatory variant in a second proband ablates this enhancer activity in SaOS2 cells.","method":"Whole-exome sequencing, microarray gene expression, enhancer reporter assay in SaOS2 cells, Sanger sequencing","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional enhancer assay, expression analysis in disease model, genetic evidence in patients, single study","pmids":["28301468"],"is_preprint":false},{"year":2017,"finding":"Either silencing or overexpression of migfilin in mouse embryos (in utero electroporation) disrupted neocortical neuronal migration. Migfilin silencing in cultured hippocampal neurons impaired neurite elongation. Migfilin was detected specifically in embryonic and perinatal stages of mouse brain.","method":"In utero electroporation (gain/loss of function), primary hippocampal neuron culture with siRNA, immunohistochemistry","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional in vivo manipulation with defined neuronal phenotypes, single lab","pmids":["29114925"],"is_preprint":false},{"year":2020,"finding":"Migfilin-knockout mice showed approximately doubled tail-bleeding time and prolonged FeCl3-induced thrombosis occlusion time. Migfilin deficiency impaired platelet thrombus formation on collagen, platelet aggregation, and dense-granule secretion. Functional defects were associated with compromised outside-in αIIbβ3 signaling (not inside-out signaling). A cell-permeable migfilin peptide harboring the filamin A binding sequence rescued defective function. In resting platelets migfilin does not influence filamin A–β3 binding, but migfilin hampers re-association of filamin A with β3 during outside-in signaling.","method":"Migfilin-knockout mouse, tail-bleeding assay, FeCl3 thrombosis model, platelet aggregation assay, phosphorylation analysis of signaling molecules, cell-permeable peptide rescue","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive knockout mouse with multiple in vivo and ex vivo phenotypic readouts, peptide rescue experiment, signaling mechanism characterized, single lab with multiple orthogonal methods","pmids":["33131250"],"is_preprint":false},{"year":2024,"finding":"Migfilin promotes autophagosome-lysosome fusion by directly interacting with SNAP29 and Vamp8, facilitating assembly of the Stx17-SNAP29-Vamp8 SNARE complex. Depletion of migfilin disrupts SNAP29-mediated SNARE complex formation, blocking autophagosome-lysosome fusion and suppressing autophagic flux, ultimately inhibiting cancer cell growth. Restoration of SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects.","method":"Co-immunoprecipitation, siRNA knockdown, autophagy flux assays, SNARE complex reconstitution/reassembly experiments, cell proliferation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional rescue of SNARE complex, defined autophagic flux phenotype with multiple readouts, single lab with orthogonal methods","pmids":["39283311"],"is_preprint":false},{"year":2025,"finding":"FBLIM1 promotes liver fibrosis in bile duct ligation rats via the TGF-β signaling pathway. FBLIM1 knockdown attenuated liver fibrosis and blocked TGF-β signaling. FBLIM1 mRNA is stabilized by WTAP in an m6A-dependent manner, regulating FBLIM1 expression. In TGF-β1-stimulated hepatic stellate cells, FBLIM1 promoted cell activation and fibrosis through TGF-β signaling.","method":"Rat BDL model, siRNA knockdown in vivo and in vitro, Western blot, histopathology, m6A modification analysis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro loss-of-function with defined fibrosis phenotype, epigenetic regulation mechanism identified, single lab","pmids":["40334627"],"is_preprint":false}],"current_model":"Migfilin (FBLIM1) is a focal adhesion adaptor protein that, through its N-terminal filamin-binding domain and C-terminal LIM domains (which bind kindlin-1/2), scaffolds the connection between cell-matrix adhesion sites and the actin cytoskeleton; it acts as a molecular switch that competes with integrin beta cytoplasmic tails for filamin binding, thereby displacing filamin and enabling talin-mediated integrin activation, while also interacting with VASP to regulate actin dynamics, with Src to promote survival signaling, with SNAP29/Vamp8 to drive autophagosome-lysosome fusion, and with transcriptional/signaling pathways (including GSK-3β/β-catenin, ERK, Akt, and TGF-β/Smad3) in contexts of bone remodeling, cardiac hypertrophy, liver fibrosis, neuronal migration, and platelet outside-in signaling."},"narrative":{"mechanistic_narrative":"FBLIM1 (migfilin) is a focal-adhesion adaptor protein that scaffolds the connection between cell-matrix adhesion sites and the actin cytoskeleton, bridging filamin and the kindlin family to regulate cell shape, adhesion, and migration [PMID:12679033]. Its N-terminal region binds all three filamins through a site on IgFLNa21 that overlaps the integrin beta-tail binding site, allowing migfilin to compete with integrin tails, displace filamin, and thereby license talin-mediated integrin activation — a molecular-switch function established by crystallography, NMR, and cell-based activation assays [PMID:18829455, PMID:19074766, PMID:22043318]. Its C-terminal LIM domains bind kindlin-1/2 and dictate focal-adhesion localization and dynamics, while the N-terminal filamin interaction drives association with actin-rich stress fibers [PMID:12679033, PMID:24165133]. Migfilin additionally recruits VASP via a proline-rich LPPPPP motif to tune actin-dependent migration biphasically [PMID:16531412] and binds Src to relieve its autoinhibition, promoting survival signaling and protecting cells from detachment-induced apoptosis [PMID:19833732]. Beyond adhesion, migfilin localizes to cadherin-based cell-cell junctions in association with beta-catenin [PMID:15671069] and drives autophagosome-lysosome fusion by interacting with SNAP29 and Vamp8 to promote assembly of the Stx17-SNAP29-Vamp8 SNARE complex [PMID:39283311]. Constitutive knockout mice are developmentally normal but reveal context-specific roles: severe osteopenia with elevated RANKL via ERK1/2 [PMID:22556421], attenuated pressure-overload cardiac hypertrophy with reduced Akt activation [PMID:25852081], and impaired platelet outside-in alphaIIbbeta3 signaling causing bleeding and thrombosis defects [PMID:33131250]. A homozygous mutation in the FBLIM1 filamin-binding domain is associated with chronic recurrent multifocal osteomyelitis (CRMO) [PMID:28301468].","teleology":[{"year":2003,"claim":"Established migfilin as a focal-adhesion adaptor that physically bridges kindlin (Mig-2) and filamin, defining the architecture by which it links adhesions to actin.","evidence":"Co-IP, pulldown, siRNA knockdown and dominant-negative overexpression with fluorescence microscopy in cultured cells","pmids":["12679033"],"confidence":"High","gaps":["Did not resolve the structural basis of either interaction","Did not define downstream signaling consequences"]},{"year":2005,"claim":"Showed migfilin function extends beyond cell-matrix adhesion to cadherin-based cell-cell junctions, linking it to adherens junction organization.","evidence":"siRNA knockdown, immunoelectron microscopy, detergent fractionation and domain deletion mutants in epithelial/endothelial cells","pmids":["15671069"],"confidence":"High","gaps":["Direct binding partner at junctions (beta-catenin association) not biochemically mapped","Functional consequence for tissue integrity in vivo untested"]},{"year":2006,"claim":"Identified VASP as a direct migfilin partner and explained migfilin's biphasic control of migration through recruitment of actin-regulatory machinery.","evidence":"Co-IP, site-directed mutagenesis of the LPPPPP motif, siRNA knockdown and migration assays","pmids":["16531412"],"confidence":"High","gaps":["Molecular basis of the biphasic dose-response not resolved","In vivo relevance untested"]},{"year":2008,"claim":"Resolved the structural basis of migfilin-filamin binding and established the molecular-switch model whereby migfilin competes with integrin tails to enable integrin activation.","evidence":"X-ray crystallography, NMR, competition binding assays and cell-based integrin activation assays","pmids":["18829455","19074766"],"confidence":"High","gaps":["Cellular conditions triggering the switch not defined","Quantitative affinity hierarchy across tissues unknown"]},{"year":2008,"claim":"Placed migfilin within a kindlin-1/kindlin-2 adhesion module and showed kindlin-1 can act independently of migfilin.","evidence":"Reciprocal Co-IP, confocal microscopy and siRNA knockdown in keratinocytes","pmids":["18528435"],"confidence":"Medium","gaps":["Single lab, limited mechanistic follow-up","Functional consequence of the tripartite complex not defined"]},{"year":2009,"claim":"Connected migfilin to survival signaling by showing it directly activates Src and protects against detachment-induced apoptosis.","evidence":"Co-IP, pulldown, knockdown/overexpression and apoptosis assays","pmids":["19833732"],"confidence":"Medium","gaps":["Src activation mechanism mapped biochemically but not structurally","In vivo survival role untested"]},{"year":2011,"claim":"Refined the filamin mechanism by showing migfilin relieves filamin autoinhibition and engages multiple repeats simultaneously, implying mechanical regulation of filamin.","evidence":"NMR spectroscopy and binding assays on filamin repeats 19/21","pmids":["21524097"],"confidence":"Medium","gaps":["No cellular functional validation of the mechanical-stretch model","Single lab"]},{"year":2011,"claim":"Demonstrated migfilin overcomes filamin-mediated suppression of multiple integrin classes and is required for endothelial spreading and migration.","evidence":"Flow cytometry integrin activation, siRNA knockdown and migration assays in endothelial cells and neutrophils","pmids":["22043318"],"confidence":"Medium","gaps":["In vivo vascular relevance untested","Single lab"]},{"year":2011,"claim":"Tested the in vivo necessity of migfilin, revealing functional redundancy during development and homeostasis despite the strong in vitro adhesion phenotypes.","evidence":"Constitutive knockout mouse with adhesion, spreading, integrin activation and wound migration readouts","pmids":["21224394"],"confidence":"High","gaps":["Compensating factors not identified","Tissue-stress contexts not probed in this study"]},{"year":2012,"claim":"Revealed a non-adhesion role in transcriptional/signaling control by showing migfilin promotes GSK-3beta-dependent beta-catenin degradation in cancer cells.","evidence":"Overexpression/knockdown, GSK-3beta and proteasome inhibitors, Co-IP and Western blot in esophageal cancer cells","pmids":["22246236"],"confidence":"Medium","gaps":["Direct vs scaffold-mediated effect on the destruction complex unresolved","In vivo tumor relevance untested"]},{"year":2012,"claim":"Uncovered a stress-context bone phenotype, defining migfilin as a regulator of osteoblast/osteoclast balance via ERK1/2-dependent RANKL control.","evidence":"Knockout mouse, primary BMSC assays, RANKL ELISA, ERK inhibitor rescue and histology","pmids":["22556421"],"confidence":"High","gaps":["Link between adhesion function and ERK/RANKL signaling not mechanistically bridged","Direct transcriptional control of RANKL not shown"]},{"year":2013,"claim":"Mapped kindlin-1/2 binding to migfilin's LIM domains and showed kindlin governs migfilin focal-adhesion recruitment and mobility.","evidence":"Pulldown, FRET, FRAP, kindlin siRNA knockdown and domain deletion mutants","pmids":["24165133"],"confidence":"High","gaps":["Structural basis of LIM-kindlin binding not resolved","Regulation of the switch between FA and stress-fiber localization unclear"]},{"year":2015,"claim":"Identified a Src-kindlin-2-migfilin positive feedback loop regulating migfilin recruitment to focal adhesions.","evidence":"Co-IP, mutagenesis of kindlin-2 Y193, kinase assays and microscopy","pmids":["26037143"],"confidence":"Medium","gaps":["Physiological trigger of the feedback loop unknown","In vivo significance untested"]},{"year":2015,"claim":"Implicated migfilin in cardiac hypertrophic remodeling, including nuclear translocation and Akt activation under pressure overload.","evidence":"Knockout mouse with transverse aortic constriction, echocardiography, immunofluorescence and Akt phosphorylation Western blot","pmids":["25852081"],"confidence":"Medium","gaps":["Nuclear function of migfilin not defined","Mechanism linking migfilin to Akt unresolved"]},{"year":2017,"claim":"Provided human genetic and regulatory evidence linking FBLIM1 to chronic recurrent multifocal osteomyelitis.","evidence":"Whole-exome sequencing, microarray in cmo model, enhancer reporter assay in SaOS2 cells","pmids":["28301468"],"confidence":"Medium","gaps":["Causality of the coding mutation not functionally proven","Single study"]},{"year":2017,"claim":"Extended migfilin function to nervous system development, showing it is required for neocortical neuronal migration and neurite elongation.","evidence":"In utero electroporation gain/loss of function and primary hippocampal neuron culture with siRNA","pmids":["29114925"],"confidence":"Medium","gaps":["Molecular partners mediating neuronal migration not identified","Bidirectional disruption mechanism unexplained"]},{"year":2020,"claim":"Defined a specific role in platelet outside-in alphaIIbbeta3 signaling, where migfilin prevents filamin A re-association with beta3.","evidence":"Knockout mouse, tail-bleeding and FeCl3 thrombosis models, aggregation/secretion assays and filamin-binding peptide rescue","pmids":["33131250"],"confidence":"High","gaps":["Spatiotemporal regulation of filamin displacement during signaling not resolved","Upstream signal controlling migfilin engagement unknown"]},{"year":2024,"claim":"Established a membrane-trafficking role by showing migfilin drives autophagosome-lysosome fusion through SNARE assembly, with consequences for cancer cell growth.","evidence":"Co-IP, siRNA knockdown, autophagy flux assays and SNARE reassembly experiments","pmids":["39283311"],"confidence":"High","gaps":["How an adhesion adaptor is recruited to the autophagic SNARE machinery unclear","Relationship to migfilin's adhesion functions undefined"]},{"year":2025,"claim":"Linked FBLIM1 to liver fibrosis via TGF-beta signaling and revealed WTAP/m6A-dependent stabilization of its mRNA as an upstream regulatory layer.","evidence":"Rat bile-duct-ligation model, in vivo/in vitro knockdown, m6A analysis and histopathology","pmids":["40334627"],"confidence":"Medium","gaps":["Direct molecular link between FBLIM1 and TGF-beta/Smad components not mapped","Single lab"]},{"year":null,"claim":"How a single focal-adhesion adaptor is partitioned between its distinct roles — integrin switch, junctional, transcriptional, autophagic, and tissue-specific signaling functions — and what determines context-specific deployment remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model reconciling adhesion vs autophagy vs nuclear roles","Regulatory inputs selecting among partners unknown","Structural basis of LIM-kindlin and migfilin-SNARE interactions not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,12,18]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6,8]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,11,14,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[17]}],"complexes":["Stx17-SNAP29-Vamp8 SNARE complex","kindlin-migfilin-filamin adhesion module"],"partners":["FLNA","FERMT2","FERMT1","VASP","SRC","SNAP29","VAMP8","CTNNB1"],"other_free_text":[]}},"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":"12679033","id":"PMC_12679033","title":"Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12679033","citation_count":312,"is_preprint":false},{"pmid":"18829455","id":"PMC_18829455","title":"Structural basis of the migfilin-filamin interaction and competition with integrin beta tails.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18829455","citation_count":97,"is_preprint":false},{"pmid":"19074766","id":"PMC_19074766","title":"Migfilin, a molecular switch in regulation of integrin activation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19074766","citation_count":94,"is_preprint":false},{"pmid":"18528435","id":"PMC_18528435","title":"Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24165133","citation_count":19,"is_preprint":false},{"pmid":"25773778","id":"PMC_25773778","title":"Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis.","date":"2015","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25773778","citation_count":16,"is_preprint":false},{"pmid":"32397996","id":"PMC_32397996","title":"Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups.","date":"2020","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32397996","citation_count":16,"is_preprint":false},{"pmid":"30129678","id":"PMC_30129678","title":"FBLIM1 enhances oral cancer malignancy via modulation of the epidermal growth factor receptor pathway.","date":"2018","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30129678","citation_count":15,"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":"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":"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},{"pmid":"29203120","id":"PMC_29203120","title":"Migfilin promotes migration and invasion in glioma by driving EGFR and MMP-2 signalings: A positive feedback loop regulation.","date":"2017","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/29203120","citation_count":10,"is_preprint":false},{"pmid":"23237804","id":"PMC_23237804","title":"Migfilin's elimination from osteoarthritic chondrocytes further promotes the osteoarthritic phenotype via β-catenin upregulation.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23237804","citation_count":9,"is_preprint":false},{"pmid":"24959381","id":"PMC_24959381","title":"Expression of migfilin is increased in esophageal cancer and represses the Akt-β-catenin activation.","date":"2014","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24959381","citation_count":9,"is_preprint":false},{"pmid":"22983390","id":"PMC_22983390","title":"Migfilin sensitizes cisplatin-induced apoptosis in human glioma cells in vitro.","date":"2012","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/22983390","citation_count":8,"is_preprint":false},{"pmid":"25852081","id":"PMC_25852081","title":"In vivo cardiac role of migfilin during experimental pressure overload.","date":"2015","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/25852081","citation_count":7,"is_preprint":false},{"pmid":"29114925","id":"PMC_29114925","title":"Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders.","date":"2017","source":"Journal of neuroscience 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University","url":"https://pubmed.ncbi.nlm.nih.gov/18583227","citation_count":0,"is_preprint":false},{"pmid":"41771455","id":"PMC_41771455","title":"Curdione alleviates renal fibrosis through Fblim1-dependent inhibition of the TGF-β1/Smad3 signaling pathway.","date":"2026","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41771455","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19266,"output_tokens":5339,"usd":0.068942,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13919,"output_tokens":5241,"usd":0.10031,"stage2_stop_reason":"end_turn"},"total_usd":0.169252,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Migfilin localizes to cell-matrix adhesions, associates with actin filaments, and is essential for cell shape modulation. Migfilin interacts with Mig-2 (kindlin/UNC-112 homolog) through its C-terminal domain and with filamin through its N-terminal domain. Mig-2 recruits migfilin to cell-matrix adhesions, while the interaction with filamin mediates migfilin's association with actin filaments.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, siRNA knockdown, dominant-negative overexpression, fluorescence microscopy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional knockdown with defined cellular phenotype, multiple orthogonal methods, independently replicated in subsequent studies\",\n      \"pmids\": [\"12679033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Migfilin localizes to cell-cell junctions in epithelial and endothelial cells in response to cadherin-mediated adhesion, forming detergent-resistant clusters associated with actin bundles. The C-terminal LIM domains mediate localization to cell-cell junctions. siRNA depletion of migfilin compromised adherens junction organization and weakened cell-cell association. Immunoelectron microscopy showed migfilin associates with beta-catenin (not desmosomes) at cell-cell junctions.\",\n      \"method\": \"siRNA knockdown, immunoelectron microscopy, confocal microscopy, detergent fractionation, domain deletion mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (immunoEM, FACS, KD with phenotype, domain mapping), single lab\",\n      \"pmids\": [\"15671069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Migfilin interacts with VASP through the VASP EVH1 domain and a single LPPPPP site (L104) in migfilin's proline-rich domain. Migfilin facilitates VASP localization to cell-matrix adhesions. Both loss and overexpression of migfilin reduce cell migration (biphasic regulation). VASP-binding defective migfilin mutants abolish migfilin-mediated regulation of cell migration.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, migration assay, fluorescence colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapped by mutagenesis, functional KD with phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16531412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"X-ray crystallography and NMR revealed the structural basis of migfilin binding to filamin. The filamin-binding site in migfilin is localized between Pro5 and Pro19, binding to the CD face of IgFLNa21 beta-sandwich. Migfilin binds all three human filamins (FLNa, -b, -c) with preference for IgFLNa21, and also more weakly to IgFLNa19 and IgFLNa22. Migfilin and integrin beta tails compete for the same binding site on IgFLNa21, suggesting migfilin can displace integrin from filamin.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, protein-protein interaction assays, competition binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus NMR plus biochemical binding assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18829455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Migfilin structurally interacts with the same region in filamin where integrin beta cytoplasmic tails bind, and this interaction dissociates filamin from integrin beta tails, thereby promoting talin-integrin interaction and integrin activation. Migfilin thus acts as a molecular switch to disconnect filamin from integrin for regulating integrin activation.\",\n      \"method\": \"Structural studies (NMR/biochemical), competition binding assays, cell-based integrin activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural and biochemical reconstitution, functional cell-based validation, corroborated by independent studies (PMID:18829455, 22043318)\",\n      \"pmids\": [\"19074766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kindlin-1 interacts with both kindlin-2 and migfilin; the three proteins co-immunoprecipitate and colocalize at focal adhesions in keratinocytes. Loss of kindlin-1 expression does not affect KIND2 or FBLIM1 gene expression or kindlin-2/migfilin protein localization, indicating kindlin-1 can function independently of kindlin-2 and migfilin.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, siRNA knockdown, immunohistochemistry\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP and colocalization, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"18528435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Migfilin directly interacts with Src kinase; the migfilin binding surface overlaps with the inhibitory intramolecular interaction sites in Src, resulting in Src activation upon migfilin binding. Loss of cell-ECM adhesion reduces migfilin levels and induces apoptosis. Migfilin overexpression desensitizes cells to detachment-induced apoptosis; migfilin depletion promotes apoptosis despite cell-ECM adhesion.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, siRNA knockdown, overexpression, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, functional KD/OE with defined apoptosis phenotype, mechanistic link to Src activation mapped, single lab\",\n      \"pmids\": [\"19833732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR spectroscopy showed that filamin autoinhibition of repeats 19 and 21 can be relieved by migfilin (or integrin), and repeats 19 and 21 can simultaneously engage ligands, suggesting migfilin mechanically stretches filamin via multisite binding to regulate cytoskeleton and integrin-mediated cell adhesion.\",\n      \"method\": \"NMR spectroscopy, binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous NMR method but single lab, no cellular functional follow-up reported in abstract\",\n      \"pmids\": [\"21524097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Flow cytometry demonstrated that filamin inhibits β1 and αIIbβ3 integrin activation, and migfilin can overcome this inhibitory effect. Migfilin can activate β1, β2, and β3 integrins in endothelial cells and neutrophils. Migfilin depletion impairs spreading and migration of endothelial cells.\",\n      \"method\": \"Flow cytometry, siRNA knockdown, cell spreading and migration assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD in primary vascular cells, flow cytometry for integrin activation, multiple integrin subtypes tested, single lab\",\n      \"pmids\": [\"22043318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In migfilin-null mice generated by genetic inactivation, development and postnatal aging were normal. Fibroblasts and keratinocytes from migfilin-null mice displayed normal spreading, adhesion, integrin expression, and integrin activation. Migration velocity of null embryonic fibroblasts was normal, but migfilin-null keratinocyte migration was slightly reduced in wound scratch assays. This indicates migfilin roles are functionally redundant during mouse development and tissue homeostasis.\",\n      \"method\": \"Genetic knockout mouse, cell spreading/adhesion assays, flow cytometry for integrin activation, wound scratch migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — constitutive knockout mouse with multiple orthogonal readouts; findings are largely negative for major developmental phenotype, single lab\",\n      \"pmids\": [\"21224394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic inactivation of FBLIM1 in mice caused severe osteopenic phenotype. FBLP-1 null bone marrow stromal cells (BMSCs) showed reduced ECM adhesion and migration. Loss of FBLP-1 impaired BMSC growth and survival, decreased osteoblast progenitor numbers and differentiation, and dramatically increased osteoclast differentiation in vivo. RANKL levels were markedly elevated in FBLP-1 null BMSCs. Loss of FBLP-1 promoted activating phosphorylation of ERK1/2, and ERK1/2 inhibition suppressed the increase of RANKL. FBLP-1 null bone marrow monocytes differentiated normally into osteoclasts when provided exogenous RANKL.\",\n      \"method\": \"Genetic knockout mouse, primary cell culture, cell adhesion/migration assays, RANKL ELISA, ERK inhibitor treatment, histology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive knockout mouse with multiple defined cellular and molecular phenotypes, pharmacological rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22556421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Migfilin promotes GSK-3β-mediated degradation of β-catenin in esophageal cancer cells. Overexpression of migfilin reduced free β-catenin levels and transcriptional activity; this was reversed by siRNA knockdown of migfilin, a Ser37 phosphorylation-deficient β-catenin mutant, GSK-3β inhibitor (LiCl), or proteasome inhibitor (MG132). Migfilin reinforced the association between β-catenin and GSK-3β.\",\n      \"method\": \"Overexpression, siRNA knockdown, GSK-3β inhibitor, proteasome inhibitor, co-immunoprecipitation, Western blot\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches, mechanistic pathway mapped, single lab\",\n      \"pmids\": [\"22246236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kindlin-1 and kindlin-2 interact with the C-terminal LIM domains of migfilin in vitro and in cells. The C-terminal LIM domains of migfilin dictate FA localization; deletion of this region reveals the N-terminal filamin-binding region drives localization to actin-rich stress fibers. Kindlin knockdown disrupts normal migfilin dynamics (FA recruitment and mobility) as shown by FRAP and FRET assays.\",\n      \"method\": \"Pulldown assays, fluorescence microscopy, FRET, FRAP, kindlin siRNA knockdown, domain deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (FRAP, FRET, pulldown, KD), domain mapping and functional consequence defined, single lab\",\n      \"pmids\": [\"24165133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kindlin-2 phosphorylation by Src at Y193 is involved in Migfilin binding to kindlin-2 and recruitment of Migfilin to focal adhesions. Src phosphorylates kindlin-2 at Y193; reciprocally, this phosphorylation activates and maintains Src kinase activity, forming a positive feedback loop involving Src, kindlin-2, and migfilin.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, kinase assays, Western blot for phosphorylation, fluorescence microscopy\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation site, functional localization and signaling readouts, single lab\",\n      \"pmids\": [\"26037143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In a migfilin knockout mouse subjected to transverse aortic constriction (TAC), migfilin-null hearts showed reduced extent of hypertrophic remodeling and maintained cardiac function longer than WT mice. Migfilin translocated into the nucleus of TAC-treated cardiomyocytes. Migfilin KO hearts showed reduced Akt activation during early response to pressure overload.\",\n      \"method\": \"Knockout mouse model, transverse aortic constriction, echocardiography, immunofluorescence for nuclear translocation, Western blot for Akt phosphorylation\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with defined cardiac phenotype, nuclear translocation shown, signaling pathway identified, single lab\",\n      \"pmids\": [\"25852081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous mutation in the filamin-binding domain of FBLIM1 was identified in a CRMO patient. Microarray analysis showed the Fblim1 ortholog is the most differentially expressed gene (downregulated >20-fold) in bone marrow macrophages from the cmo murine CRMO model. An enhancer element flanking FBLIM1 was identified; a regulatory variant in a second proband ablates this enhancer activity in SaOS2 cells.\",\n      \"method\": \"Whole-exome sequencing, microarray gene expression, enhancer reporter assay in SaOS2 cells, Sanger sequencing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional enhancer assay, expression analysis in disease model, genetic evidence in patients, single study\",\n      \"pmids\": [\"28301468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Either silencing or overexpression of migfilin in mouse embryos (in utero electroporation) disrupted neocortical neuronal migration. Migfilin silencing in cultured hippocampal neurons impaired neurite elongation. Migfilin was detected specifically in embryonic and perinatal stages of mouse brain.\",\n      \"method\": \"In utero electroporation (gain/loss of function), primary hippocampal neuron culture with siRNA, immunohistochemistry\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional in vivo manipulation with defined neuronal phenotypes, single lab\",\n      \"pmids\": [\"29114925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Migfilin-knockout mice showed approximately doubled tail-bleeding time and prolonged FeCl3-induced thrombosis occlusion time. Migfilin deficiency impaired platelet thrombus formation on collagen, platelet aggregation, and dense-granule secretion. Functional defects were associated with compromised outside-in αIIbβ3 signaling (not inside-out signaling). A cell-permeable migfilin peptide harboring the filamin A binding sequence rescued defective function. In resting platelets migfilin does not influence filamin A–β3 binding, but migfilin hampers re-association of filamin A with β3 during outside-in signaling.\",\n      \"method\": \"Migfilin-knockout mouse, tail-bleeding assay, FeCl3 thrombosis model, platelet aggregation assay, phosphorylation analysis of signaling molecules, cell-permeable peptide rescue\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive knockout mouse with multiple in vivo and ex vivo phenotypic readouts, peptide rescue experiment, signaling mechanism characterized, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33131250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Migfilin promotes autophagosome-lysosome fusion by directly interacting with SNAP29 and Vamp8, facilitating assembly of the Stx17-SNAP29-Vamp8 SNARE complex. Depletion of migfilin disrupts SNAP29-mediated SNARE complex formation, blocking autophagosome-lysosome fusion and suppressing autophagic flux, ultimately inhibiting cancer cell growth. Restoration of SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, autophagy flux assays, SNARE complex reconstitution/reassembly experiments, cell proliferation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional rescue of SNARE complex, defined autophagic flux phenotype with multiple readouts, single lab with orthogonal methods\",\n      \"pmids\": [\"39283311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBLIM1 promotes liver fibrosis in bile duct ligation rats via the TGF-β signaling pathway. FBLIM1 knockdown attenuated liver fibrosis and blocked TGF-β signaling. FBLIM1 mRNA is stabilized by WTAP in an m6A-dependent manner, regulating FBLIM1 expression. In TGF-β1-stimulated hepatic stellate cells, FBLIM1 promoted cell activation and fibrosis through TGF-β signaling.\",\n      \"method\": \"Rat BDL model, siRNA knockdown in vivo and in vitro, Western blot, histopathology, m6A modification analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro loss-of-function with defined fibrosis phenotype, epigenetic regulation mechanism identified, single lab\",\n      \"pmids\": [\"40334627\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Migfilin (FBLIM1) is a focal adhesion adaptor protein that, through its N-terminal filamin-binding domain and C-terminal LIM domains (which bind kindlin-1/2), scaffolds the connection between cell-matrix adhesion sites and the actin cytoskeleton; it acts as a molecular switch that competes with integrin beta cytoplasmic tails for filamin binding, thereby displacing filamin and enabling talin-mediated integrin activation, while also interacting with VASP to regulate actin dynamics, with Src to promote survival signaling, with SNAP29/Vamp8 to drive autophagosome-lysosome fusion, and with transcriptional/signaling pathways (including GSK-3β/β-catenin, ERK, Akt, and TGF-β/Smad3) in contexts of bone remodeling, cardiac hypertrophy, liver fibrosis, neuronal migration, and platelet outside-in signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBLIM1 (migfilin) is a focal-adhesion adaptor protein that scaffolds the connection between cell-matrix adhesion sites and the actin cytoskeleton, bridging filamin and the kindlin family to regulate cell shape, adhesion, and migration [#0]. Its N-terminal region binds all three filamins through a site on IgFLNa21 that overlaps the integrin beta-tail binding site, allowing migfilin to compete with integrin tails, displace filamin, and thereby license talin-mediated integrin activation \\u2014 a molecular-switch function established by crystallography, NMR, and cell-based activation assays [#3, #4, #8]. Its C-terminal LIM domains bind kindlin-1/2 and dictate focal-adhesion localization and dynamics, while the N-terminal filamin interaction drives association with actin-rich stress fibers [#0, #12]. Migfilin additionally recruits VASP via a proline-rich LPPPPP motif to tune actin-dependent migration biphasically [#2] and binds Src to relieve its autoinhibition, promoting survival signaling and protecting cells from detachment-induced apoptosis [#6]. Beyond adhesion, migfilin localizes to cadherin-based cell-cell junctions in association with beta-catenin [#1] and drives autophagosome-lysosome fusion by interacting with SNAP29 and Vamp8 to promote assembly of the Stx17-SNAP29-Vamp8 SNARE complex [#18]. Constitutive knockout mice are developmentally normal but reveal context-specific roles: severe osteopenia with elevated RANKL via ERK1/2 [#10], attenuated pressure-overload cardiac hypertrophy with reduced Akt activation [#14], and impaired platelet outside-in alphaIIbbeta3 signaling causing bleeding and thrombosis defects [#17]. A homozygous mutation in the FBLIM1 filamin-binding domain is associated with chronic recurrent multifocal osteomyelitis (CRMO) [#15].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established migfilin as a focal-adhesion adaptor that physically bridges kindlin (Mig-2) and filamin, defining the architecture by which it links adhesions to actin.\",\n      \"evidence\": \"Co-IP, pulldown, siRNA knockdown and dominant-negative overexpression with fluorescence microscopy in cultured cells\",\n      \"pmids\": [\"12679033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of either interaction\", \"Did not define downstream signaling consequences\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed migfilin function extends beyond cell-matrix adhesion to cadherin-based cell-cell junctions, linking it to adherens junction organization.\",\n      \"evidence\": \"siRNA knockdown, immunoelectron microscopy, detergent fractionation and domain deletion mutants in epithelial/endothelial cells\",\n      \"pmids\": [\"15671069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner at junctions (beta-catenin association) not biochemically mapped\", \"Functional consequence for tissue integrity in vivo untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified VASP as a direct migfilin partner and explained migfilin's biphasic control of migration through recruitment of actin-regulatory machinery.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis of the LPPPPP motif, siRNA knockdown and migration assays\",\n      \"pmids\": [\"16531412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the biphasic dose-response not resolved\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the structural basis of migfilin-filamin binding and established the molecular-switch model whereby migfilin competes with integrin tails to enable integrin activation.\",\n      \"evidence\": \"X-ray crystallography, NMR, competition binding assays and cell-based integrin activation assays\",\n      \"pmids\": [\"18829455\", \"19074766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular conditions triggering the switch not defined\", \"Quantitative affinity hierarchy across tissues unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed migfilin within a kindlin-1/kindlin-2 adhesion module and showed kindlin-1 can act independently of migfilin.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal microscopy and siRNA knockdown in keratinocytes\",\n      \"pmids\": [\"18528435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, limited mechanistic follow-up\", \"Functional consequence of the tripartite complex not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected migfilin to survival signaling by showing it directly activates Src and protects against detachment-induced apoptosis.\",\n      \"evidence\": \"Co-IP, pulldown, knockdown/overexpression and apoptosis assays\",\n      \"pmids\": [\"19833732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Src activation mechanism mapped biochemically but not structurally\", \"In vivo survival role untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refined the filamin mechanism by showing migfilin relieves filamin autoinhibition and engages multiple repeats simultaneously, implying mechanical regulation of filamin.\",\n      \"evidence\": \"NMR spectroscopy and binding assays on filamin repeats 19/21\",\n      \"pmids\": [\"21524097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cellular functional validation of the mechanical-stretch model\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated migfilin overcomes filamin-mediated suppression of multiple integrin classes and is required for endothelial spreading and migration.\",\n      \"evidence\": \"Flow cytometry integrin activation, siRNA knockdown and migration assays in endothelial cells and neutrophils\",\n      \"pmids\": [\"22043318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo vascular relevance untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Tested the in vivo necessity of migfilin, revealing functional redundancy during development and homeostasis despite the strong in vitro adhesion phenotypes.\",\n      \"evidence\": \"Constitutive knockout mouse with adhesion, spreading, integrin activation and wound migration readouts\",\n      \"pmids\": [\"21224394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensating factors not identified\", \"Tissue-stress contexts not probed in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a non-adhesion role in transcriptional/signaling control by showing migfilin promotes GSK-3beta-dependent beta-catenin degradation in cancer cells.\",\n      \"evidence\": \"Overexpression/knockdown, GSK-3beta and proteasome inhibitors, Co-IP and Western blot in esophageal cancer cells\",\n      \"pmids\": [\"22246236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold-mediated effect on the destruction complex unresolved\", \"In vivo tumor relevance untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Uncovered a stress-context bone phenotype, defining migfilin as a regulator of osteoblast/osteoclast balance via ERK1/2-dependent RANKL control.\",\n      \"evidence\": \"Knockout mouse, primary BMSC assays, RANKL ELISA, ERK inhibitor rescue and histology\",\n      \"pmids\": [\"22556421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between adhesion function and ERK/RANKL signaling not mechanistically bridged\", \"Direct transcriptional control of RANKL not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped kindlin-1/2 binding to migfilin's LIM domains and showed kindlin governs migfilin focal-adhesion recruitment and mobility.\",\n      \"evidence\": \"Pulldown, FRET, FRAP, kindlin siRNA knockdown and domain deletion mutants\",\n      \"pmids\": [\"24165133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LIM-kindlin binding not resolved\", \"Regulation of the switch between FA and stress-fiber localization unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a Src-kindlin-2-migfilin positive feedback loop regulating migfilin recruitment to focal adhesions.\",\n      \"evidence\": \"Co-IP, mutagenesis of kindlin-2 Y193, kinase assays and microscopy\",\n      \"pmids\": [\"26037143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger of the feedback loop unknown\", \"In vivo significance untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated migfilin in cardiac hypertrophic remodeling, including nuclear translocation and Akt activation under pressure overload.\",\n      \"evidence\": \"Knockout mouse with transverse aortic constriction, echocardiography, immunofluorescence and Akt phosphorylation Western blot\",\n      \"pmids\": [\"25852081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear function of migfilin not defined\", \"Mechanism linking migfilin to Akt unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided human genetic and regulatory evidence linking FBLIM1 to chronic recurrent multifocal osteomyelitis.\",\n      \"evidence\": \"Whole-exome sequencing, microarray in cmo model, enhancer reporter assay in SaOS2 cells\",\n      \"pmids\": [\"28301468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of the coding mutation not functionally proven\", \"Single study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended migfilin function to nervous system development, showing it is required for neocortical neuronal migration and neurite elongation.\",\n      \"evidence\": \"In utero electroporation gain/loss of function and primary hippocampal neuron culture with siRNA\",\n      \"pmids\": [\"29114925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners mediating neuronal migration not identified\", \"Bidirectional disruption mechanism unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a specific role in platelet outside-in alphaIIbbeta3 signaling, where migfilin prevents filamin A re-association with beta3.\",\n      \"evidence\": \"Knockout mouse, tail-bleeding and FeCl3 thrombosis models, aggregation/secretion assays and filamin-binding peptide rescue\",\n      \"pmids\": [\"33131250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatiotemporal regulation of filamin displacement during signaling not resolved\", \"Upstream signal controlling migfilin engagement unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a membrane-trafficking role by showing migfilin drives autophagosome-lysosome fusion through SNARE assembly, with consequences for cancer cell growth.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, autophagy flux assays and SNARE reassembly experiments\",\n      \"pmids\": [\"39283311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an adhesion adaptor is recruited to the autophagic SNARE machinery unclear\", \"Relationship to migfilin's adhesion functions undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked FBLIM1 to liver fibrosis via TGF-beta signaling and revealed WTAP/m6A-dependent stabilization of its mRNA as an upstream regulatory layer.\",\n      \"evidence\": \"Rat bile-duct-ligation model, in vivo/in vitro knockdown, m6A analysis and histopathology\",\n      \"pmids\": [\"40334627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FBLIM1 and TGF-beta/Smad components not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single focal-adhesion adaptor is partitioned between its distinct roles \\u2014 integrin switch, junctional, transcriptional, autophagic, and tissue-specific signaling functions \\u2014 and what determines context-specific deployment remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model reconciling adhesion vs autophagy vs nuclear roles\", \"Regulatory inputs selecting among partners unknown\", \"Structural basis of LIM-kindlin and migfilin-SNARE interactions not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 12, 18]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 11, 14, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"Stx17-SNAP29-Vamp8 SNARE complex\",\n      \"kindlin-migfilin-filamin adhesion module\"\n    ],\n    \"partners\": [\n      \"FLNA\",\n      \"FERMT2\",\n      \"FERMT1\",\n      \"VASP\",\n      \"SRC\",\n      \"SNAP29\",\n      \"VAMP8\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}