{"gene":"FLNA","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1993,"finding":"The ABP-280 filamin gene (FLN/FLNA) was mapped to Xq28 by Southern blot analysis of somatic cell hybrid lines and fluorescence in situ hybridization, localizing it within a 200-kb region centromeric to G6PD and telomeric to the color vision locus.","method":"Southern blot of somatic cell hybrids, FISH","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal mapping methods (somatic cell hybrid Southern blot + FISH), replicated by cosmid/YAC mapping","pmids":["8406501"],"is_preprint":false},{"year":1994,"finding":"The human FLNA (FLN1) gene comprises 47 exons spanning ~26 kb; the actin-binding domain is encoded by exons 2–5; the 96-amino-acid rod repeats are encoded by the remaining 42 exons; and exon 29 encodes an alternatively spliced 8-amino-acid segment interrupting repeat 15.","method":"Genomic cloning and exon-intron sequencing","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete gene structure determined by direct sequencing; foundational structural paper","pmids":["8088819"],"is_preprint":false},{"year":2006,"finding":"Complete loss of Flna in mice causes embryonic lethality with severe cardiac and vascular defects; Flna-null embryos display abnormal adherens junctions and aberrant endothelial/epithelial organization, demonstrating an essential role for FLNA in intercellular junctions and vascular development rather than in general cell migration.","method":"Conditional and complete knockout mouse model; histology; immunostaining of adherens junction markers","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype (adherens junction disruption), cardiac/vascular structural readout, multiple tissues examined","pmids":["17172441"],"is_preprint":false},{"year":2010,"finding":"FlnA binds to the protein tyrosine kinase Syk at immunoglobulin-like repeat 5 of FlnA; loss of this interaction in FlnA-null platelets severely impairs ITAM- and ITAM-like-mediated signaling (Syk and PLCγ2 phosphorylation), platelet spreading, α-granule secretion, and integrin αIIbβ3 activation.","method":"Platelet-specific conditional KO (GATA1-Cre); Co-IP mapping of FlnA–Syk interaction to repeat 5; functional platelet assays (spreading, secretion, tyrosine phosphorylation)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction mapping with domain-level resolution, clean conditional KO with multiple orthogonal functional readouts","pmids":["20713593"],"is_preprint":false},{"year":2010,"finding":"FLN-1/filamin in C. elegans is required to maintain actin filament organization in the spermatheca and uterus, and genetic epistasis with phospholipase PLC-1 places both proteins in the same pathway controlling embryo exit from the spermatheca.","method":"Deletion allele and RNAi depletion; double-mutant epistasis analysis; fluorescence colocalization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined phenotype plus genetic epistasis, single lab","pmids":["20707996"],"is_preprint":false},{"year":2011,"finding":"FlnA-null megakaryocytes prematurely release large, fragile platelets; FlnA stabilizes the platelet von Willebrand factor receptor GPIbα by providing cytoskeletal linkage, as shown by normal GPIbα surface expression on null megakaryocytes but decreased expression and increased ADAM17/MMP9-mediated degradation on null platelets.","method":"Megakaryocyte-specific conditional KO (PF4-Cre); flow cytometry; clodronate liposome macrophage ablation; surface receptor expression analysis; western blot for metalloproteinases","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with mechanistic dissection of GPIbα stabilization, multiple orthogonal methods","pmids":["21652675"],"is_preprint":false},{"year":2014,"finding":"FLNA overexpression in Tsc1-null neurons is driven by MEK1/2–ERK1/2 signaling (not mTOR), and elevated FLNA causes abnormal dendritic complexity; knockdown of FLNA in Tsc1-null neurons in vivo prevents dendritic abnormalities, placing FLNA downstream of MEK–ERK in the TSC dendritic pathology pathway.","method":"In utero electroporation (loss- and gain-of-function); conditional Tsc1-null mouse; MEK inhibitor pharmacology; in vivo FLNA knockdown with phenotypic rescue","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic manipulations in vivo with pharmacological confirmation, clean epistasis between MEK-ERK and FLNA","pmids":["25277454"],"is_preprint":false},{"year":2014,"finding":"FLNA is required for SST2 (somatostatin receptor 2) signaling and receptor stabilization in somatotroph tumor cells: FLNA silencing abolishes SST2-induced cyclin D1 reduction and caspase-3/7 activation; a FLNA dominant-negative mutant blocking SST2–FLNA binding reduces SST2 expression after prolonged agonist exposure; FLNA also scaffolds Gαi and partner proteins to SST2 to mediate ERK1/2 inhibition and apoptosis.","method":"siRNA silencing; dominant-negative FLNA mutant overexpression; caspase activity assay; ERK1/2 phosphorylation assay; cell proliferation assay in human GH-secreting tumor cells and GH3/GH4C1 rat cell lines","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (siRNA + dominant-negative), multiple functional readouts (proliferation, apoptosis, signaling), human and rodent models","pmids":["24828612"],"is_preprint":false},{"year":2015,"finding":"FlnA binds PACSIN2 via FlnA immunoglobulin-like repeat 20 interacting with the tip of PACSIN2's F-BAR domain; this interaction enhances PACSIN2 F-BAR-mediated membrane tubulation in vitro and is required for proper demarcation membrane system (DMS) formation and PACSIN2 localization in megakaryocytes and platelets.","method":"Co-IP (human platelets); domain-mapping of the FlnA–PACSIN2 interaction; in vitro membrane tubulation assay; Flna-null platelet/MK imaging; EGFP-PACSIN2 localization in wild-type vs Flna-null MKs","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro tubulation assay plus domain-resolved Co-IP, confirmed in null cells with live imaging","pmids":["25838348"],"is_preprint":false},{"year":2015,"finding":"MVP-associated FLNA missense mutations (G288R, P637Q, H743P) in repeats 1–8 abolish binding to the tyrosine phosphatase PTPN12 (PTP-PEST), identified by yeast two-hybrid screen, and impair activation of PTPN12 substrates Src and p190RhoGAP, linking FLNA to integrin/focal adhesion signaling via PTPN12.","method":"Yeast two-hybrid screen; pull-down; Co-IP; phosphorylation assays for Src and p190RhoGAP","journal":"Journal of cardiovascular development and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP and downstream signaling readouts, single lab","pmids":["26594644"],"is_preprint":false},{"year":2017,"finding":"FlnA physically interacts with FlnB in chondrocyte cytoplasm; FlnA more strongly binds and activates RhoA whereas FlnB indirectly inhibits RhoA; FlnA loss decreases β1-integrin expression while FlnB loss promotes it, demonstrating antagonistic roles of the two filamins in RhoA activation, integrin expression, actin stress fiber formation, and cell spreading.","method":"Co-IP (physical interaction); RhoA activation assay; integrin expression (western blot/flow cytometry); actin staining; fibronectin stimulation in null cells; cell spreading assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multiple functional assays, single lab","pmids":["28175289"],"is_preprint":false},{"year":2017,"finding":"Two FLNA transcripts differing by 28 N-terminal residues (initiated at ATG+1 and ATG+82) are expressed in a tissue-specific manner; the longer isoform (ATG+1) predominates in intestinal smooth muscle, and mutations that selectively eliminate this isoform cause congenital intestinal pseudo-obstruction (CIPO) without brain or cardiac involvement, mechanistically explaining tissue-specific phenotypes.","method":"RNA-seq; cDNA analysis; isoform-specific expression in patient fibroblasts and intestinal smooth muscle; identification of three transcription start sites","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus patient-level isoform analysis with genotype-phenotype correlation, single lab","pmids":["29024177"],"is_preprint":false},{"year":2018,"finding":"PKA phosphorylates FLNA at S2152 (promoted by cAMP), and SST2 agonist stimulation decreases this phosphorylation; phosphomimetic S2152D FLNA abolishes SST2 antitumoral effects (inhibition of proliferation, apoptosis induction, migration inhibition via RhoA/cofilin), while S2152A FLNA is recruited to activated SST2 normally; S2152D FLNA constitutively binds SST2 but prevents Gαi recruitment, blocking signal transduction.","method":"Phosphomimetic/phosphodeficient FLNA mutant overexpression; Co-IP; immunofluorescence; proliferation, apoptosis, and migration assays; RhoA activation assay; cofilin phosphorylation assay in GH3/GH4C1 and primary somatotroph cells","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of specific phosphosite with multiple orthogonal functional readouts, mechanistic dissection of phosphorylation effect on receptor coupling","pmids":["30098401"],"is_preprint":false},{"year":2018,"finding":"Single-molecule microscopy shows SSTR2 and FLNA undergo transient interactions preferentially along actin fibers at the plasma membrane; these interactions restrain SSTR2 diffusion, promote agonist-induced SSTR2 clustering and recruitment to clathrin-coated pits, and are required for SSTR2 internalization; a dominant-negative FLNA fragment disrupting SSTR2–FLNA binding increases SSTR2 mobility and impairs clustering and internalization.","method":"Fast multicolor single-molecule microscopy in living cells; dominant-negative FLNA fragment; SSTR2 diffusion analysis; clathrin-coated pit recruitment assay","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule live imaging with dominant-negative perturbation, quantitative mechanistic dissection at nanoscale resolution","pmids":["29931263"],"is_preprint":false},{"year":2015,"finding":"A missense mutation (p.Gly2593Glu) in the FLNA repeat 24 dimerization interface abolishes homodimerization of isolated repeat 24 in vitro, but extended repeat 16–24 constructs retain dimerization, implying additional non-canonical interactions contribute to FLNA homodimerization.","method":"Co-immunoprecipitation; in vitro cross-linking studies; gel filtration chromatography of repeat 24 and repeat 16–24 constructs","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — three orthogonal in vitro methods (Co-IP, crosslinking, gel filtration) in single study","pmids":["25686753"],"is_preprint":false},{"year":2021,"finding":"TRIM44 deubiquitinates p62 (sequestosome 1), promoting its oligomerization and cytoplasmic retention, which prevents p62-mediated nuclear degradation of FLNA and 53BP1, thereby increasing nuclear FLNA levels and DNA damage repair capacity.","method":"TRIM44 siRNA knockdown; western blot; subcellular fractionation; irradiation-induced DNA damage assay; co-IP for TRIM44–p62 interaction","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue experiments linking p62 deubiquitination to nuclear FLNA retention, single lab","pmids":["34211088"],"is_preprint":false},{"year":2021,"finding":"FLNA interacts with ANXA2 (annexin A2), and together they activate Wnt pathway signaling to promote gefitinib resistance in non-small-cell lung cancer; SP1 transcription factor promotes FLNA transcriptional activation; FLNA knockdown restores gefitinib sensitivity in vitro and in vivo.","method":"Co-IP (FLNA–ANXA2 interaction); ChIP (SP1 binding to FLNA promoter); CCK-8/flow cytometry; xenograft mouse model; western blot for Wnt pathway components","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus ChIP for upstream regulation plus in vivo rescue, single lab","pmids":["34018148"],"is_preprint":false},{"year":2022,"finding":"TRIM44 interacts with FLNA and facilitates its stability through deubiquitination; FLNA is required for TRIM44-mediated upregulation of BRCA1 expression and homologous recombination repair, placing FLNA upstream of BRCA1 in a TRIM44/FLNA/BRCA1 axis that confers cisplatin resistance in lung adenocarcinoma.","method":"Co-IP (TRIM44–FLNA interaction); FLNA siRNA; BRCA1 depletion rescue experiment; immunofluorescence; xenograft model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus epistatic rescue experiment (BRCA1 depletion reverses TRIM44 effect), single lab","pmids":["35541909"],"is_preprint":false},{"year":2023,"finding":"ULK kinase phosphorylates the autophagosomal SNARE STX17 at S289; FLNA acts as a linker between ATG8 family proteins and STX17, recruiting STX17 to autophagosomes; STX17 S289 phosphorylation promotes interaction with FLNA, enabling STX17 recruitment to autophagosomes and facilitating autophagosome–lysosome fusion; disease-causative FLNA mutations in the ATG8- and STX17-binding regions disrupt these interactions and impair fusion.","method":"Phospho-site mapping (ULK→STX17 S289); Co-IP (FLNA–ATG8, FLNA–STX17); autophagosome–lysosome fusion assay; disease-mutant FLNA constructs; subcellular localization studies","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phospho-site mutagenesis combined with Co-IP interaction mapping and functional fusion assay, with disease-mutation validation","pmids":["37389864"],"is_preprint":false},{"year":2023,"finding":"WTAP-mediated N6-methyladenosine (m6A) modification of FLNA mRNA leads to post-transcriptional repression of FLNA expression, and the WTAP/FLNA axis inhibits autophagy in colon cancer cells.","method":"m6A dot blot hybridization; methylated RNA immunoprecipitation (MeRIP); dual-luciferase assay; RNA immunoprecipitation; western blot for FLNA and autophagy markers; rescue experiments","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA-modification assays (MeRIP, RIP) plus functional rescue, single lab","pmids":["36849408"],"is_preprint":false},{"year":2024,"finding":"FLNA regulates Wee1 kinase protein levels by promoting its proteasomal degradation (via phosphorylation at Ser123); FLNA knockdown increases Wee1 and p-CDK1/cyclin B1 whereas FLNA overexpression increases p-Wee1(Ser123) and reduces Wee1 protein, reversed by lactacystin (proteasome inhibitor), placing FLNA as a negative regulator of Wee1 in adrenocortical carcinoma cells.","method":"FLNA knockdown and overexpression; western blot for Wee1, p-CDK1, cyclin B1, p-Wee1(Ser123); lactacystin proteasome inhibitor treatment; proliferation and apoptosis assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic evidence for proteasome-dependent Wee1 degradation regulated by FLNA, single lab","pmids":["39528354"],"is_preprint":false},{"year":2024,"finding":"FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein ARHGAP24, regulating dendritogenesis and spinogenesis in cortical pyramidal neurons; conditional Flna depletion from pyramidal neurons disrupts excitatory/inhibitory input balance.","method":"Conditional in utero electroporation of Cre in Flnaflox/flox mice; RAC1 activation assay; cofilin phosphorylation assay; Co-IP or interaction assay for FLNA–ARHGAP24; dendritic morphology quantification","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional neuronal KO with specific molecular mechanism (ARHGAP24–RAC1–cofilin axis), single lab","pmids":["38852754"],"is_preprint":false},{"year":2015,"finding":"A loss-of-function FLNA mutation inducing in-frame exon 40 skipping produces a mutant FLNA missing 41 internal amino acids that retains binding affinity to integrin and capacity to induce focal adhesions comparable to wild-type protein, demonstrating that this internal region is dispensable for integrin binding and focal adhesion formation.","method":"Whole-exome sequencing; RT-PCR/cDNA characterization of exon skipping; functional assay of integrin binding and focal adhesion formation for mutant vs wild-type FLNA","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay of mutant protein (integrin binding + focal adhesion), single study","pmids":["26059841"],"is_preprint":false},{"year":2017,"finding":"FLNA colocalizes with Rap1-GTPase in cellular protrusions of pulmonary neuroendocrine tumor cells; FLNA silencing up-regulates Rap1 expression, and Rap1 silencing prevents the FLNA-silencing-induced increase in cell adhesion and decrease in cell migration, placing Rap1 downstream of FLNA in the regulation of these processes.","method":"siRNA silencing; immunofluorescence colocalization; Rap1 western blot; cell adhesion and migration assays; epistasis via double knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic double-knockdown plus colocalization, single lab","pmids":["29100390"],"is_preprint":false},{"year":2020,"finding":"FLNA directly interacts with Smad2, enhancing c-Met promoter activity; c-Met–AKT signaling phosphorylates FLNA at Ser2152, and this phosphorylation is correlated with EMT; co-immunoprecipitation confirmed FLNA–Smad2 interaction; FLNA knockdown reduces EMT and metastasis in colorectal cancer cells in vivo.","method":"Co-immunoprecipitation (FLNA–Smad2); luciferase reporter assay (c-Met promoter); orthotopic CRC mouse model; western blot for EMT markers and pFLNA(Ser2152)","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus luciferase reporter plus in vivo model, single lab","pmids":["32195017"],"is_preprint":false}],"current_model":"FLNA encodes a large dimeric actin-crosslinking scaffold protein that physically links transmembrane receptors (GPIbα, integrins, SST2/SSTR2) to the actin cytoskeleton via its 24 immunoglobulin-like repeats, and serves as a signaling hub by recruiting and regulating kinases (Syk, RhoA, RAC1–cofilin via ARHGAP24), phosphatases (PTPN12), and G-proteins (Gαi, Rap1); its scaffold function is regulated by PKA-mediated phosphorylation at Ser2152 and by TRIM44-mediated deubiquitination (affecting nuclear levels and DNA repair), while it also participates in autophagosome maturation by bridging ATG8 proteins to STX17 to enable autophagosome–lysosome fusion; loss-of-function disrupts adherens junctions, neuronal migration, platelet biogenesis and ITAM signaling, smooth muscle layering, and dendritic morphogenesis, whereas gain-of-function missense mutations cause skeletal dysplasias, collectively explaining the broad developmental and signaling roles of this protein."},"narrative":{"mechanistic_narrative":"FLNA encodes a large dimeric actin-crosslinking scaffold built from an N-terminal actin-binding domain and 24 immunoglobulin-like repeats, whose homodimerization is mediated by repeat 24 together with additional non-canonical contacts within repeats 16–24 [PMID:8088819, PMID:25686753]. It is essential for the integrity of intercellular junctions and vascular/cardiac development, with complete loss in mice causing embryonic lethality and disrupted adherens junctions [PMID:17172441]. The protein operates as a signaling hub that physically links transmembrane receptors to the actin cytoskeleton and the Rho-GTPase machinery: it binds the tyrosine kinase Syk at repeat 5 to drive ITAM-mediated platelet activation [PMID:20713593], stabilizes the GPIbα receptor against ADAM17/MMP9-mediated proteolysis during platelet biogenesis [PMID:21652675], and tethers the F-BAR protein PACSIN2 via repeat 20 to shape the megakaryocyte demarcation membrane system [PMID:25838348]. Through differential coupling to RhoA and β1-integrin it acts antagonistically to FLNB in controlling stress fibers and cell spreading [PMID:28175289], and it directs cytoskeletal remodeling via PTPN12/Src/p190RhoGAP [PMID:26594644], Rap1 [PMID:29100390], and an ARHGAP24–RAC1–cofilin axis governing dendritogenesis [PMID:38852754]. FLNA scaffolds somatostatin receptor SST2/SSTR2 signaling, restraining receptor diffusion and clustering at clathrin-coated pits to enable internalization and Gαi-coupled antitumoral signaling, a function gated by PKA phosphorylation at Ser2152 that uncouples Gαi recruitment [PMID:30098401, PMID:29931263]. It additionally bridges ATG8-family proteins to the SNARE STX17 to promote autophagosome–lysosome fusion [PMID:37389864]. FLNA mutations cause tissue-specific developmental disease, including isoform-specific congenital intestinal pseudo-obstruction [PMID:29024177], and elevated FLNA downstream of MEK–ERK drives dendritic pathology in Tsc1-null neurons [PMID:25277454].","teleology":[{"year":1994,"claim":"Establishing the gene's domain architecture defined FLNA as a modular actin-binding protein, framing all later structure-function work.","evidence":"Genomic cloning and exon-intron sequencing of the 47-exon human gene","pmids":["8088819"],"confidence":"High","gaps":["Does not address dimerization geometry","No functional assignment to individual repeats"]},{"year":2006,"claim":"Whether FLNA's essential role lay in cell migration or junction integrity was resolved by showing null embryos die with adherens junction and vascular defects, redefining its core developmental function.","evidence":"Complete and conditional knockout mouse with histology and adherens junction immunostaining","pmids":["17172441"],"confidence":"High","gaps":["Molecular partners at the junction not identified","Tissue-specific contributions not dissected"]},{"year":2010,"claim":"Domain-resolved interaction mapping established FLNA as a direct signaling scaffold, linking Syk binding at repeat 5 to ITAM-driven platelet activation.","evidence":"Platelet-specific conditional KO with reciprocal Co-IP domain mapping and functional platelet assays","pmids":["20713593"],"confidence":"High","gaps":["Whether other repeats bind additional kinases not addressed in this study","Structural basis of the repeat 5 interface unknown"]},{"year":2011,"claim":"The mechanism of FLNA-dependent platelet biogenesis was clarified by showing FLNA stabilizes surface GPIbα against metalloprotease cleavage, explaining the macrothrombocytopenia phenotype.","evidence":"Megakaryocyte-specific conditional KO with flow cytometry, macrophage ablation, and metalloproteinase westerns","pmids":["21652675"],"confidence":"High","gaps":["Direct GPIbα-FLNA binding interface not mapped here","Link to premature platelet release not fully mechanistic"]},{"year":2015,"claim":"FLNA was shown to extend cytoskeletal scaffolding to membrane morphogenesis by tethering PACSIN2 at repeat 20 to drive demarcation membrane system formation.","evidence":"Co-IP domain mapping, in vitro membrane tubulation assay, and Flna-null megakaryocyte imaging","pmids":["25838348"],"confidence":"High","gaps":["In vivo requirement for DMS in thrombopoiesis not quantified","Regulation of the interaction unknown"]},{"year":2015,"claim":"Dimerization studies revealed that repeat 24 alone is insufficient for stable homodimerization, implying non-canonical inter-repeat contacts beyond the canonical interface.","evidence":"Co-IP, in vitro cross-linking, and gel filtration of repeat 24 and repeat 16–24 constructs","pmids":["25686753"],"confidence":"High","gaps":["Identity of the additional dimerization contacts not defined","No full-length structural model"]},{"year":2015,"claim":"A focal-adhesion-competent exon-40-skipping mutant defined an internal region dispensable for integrin binding, refining the structure-function map.","evidence":"Whole-exome sequencing, cDNA characterization, and integrin binding/focal adhesion assays","pmids":["26059841"],"confidence":"Medium","gaps":["Functional consequences in tissue context untested","Other functions of the deleted region not assessed"]},{"year":2014,"claim":"FLNA was placed in receptor signaling pathways: as a scaffold required for SST2 receptor stabilization and Gαi-mediated antitumoral signaling, and as a MEK-ERK effector in TSC dendritic pathology.","evidence":"siRNA and dominant-negative FLNA in tumor cells; in utero electroporation with MEK inhibitor pharmacology in Tsc1-null neurons","pmids":["24828612","25277454"],"confidence":"High","gaps":["Generality of receptor scaffolding beyond SST2 unclear","Transcriptional vs post-translational control of FLNA levels in neurons not fully separated"]},{"year":2015,"claim":"Yeast two-hybrid and signaling assays connected disease-associated repeat 1–8 mutations to loss of PTPN12 binding and dysregulated Src/p190RhoGAP, linking FLNA to focal adhesion signaling.","evidence":"Yeast two-hybrid, pull-down, Co-IP, and Src/p190RhoGAP phosphorylation assays","pmids":["26594644"],"confidence":"Medium","gaps":["Single-lab interaction not reciprocally validated in vivo","Causality for MVP phenotype not established"]},{"year":2017,"claim":"FLNA was shown to act antagonistically to FLNB in RhoA activation and integrin expression, and tissue-specific isoforms were linked to organ-restricted disease.","evidence":"Co-IP and RhoA/integrin functional assays in chondrocytes; RNA-seq isoform analysis with CIPO genotype-phenotype correlation","pmids":["28175289","29024177"],"confidence":"Medium","gaps":["Mechanism of differential RhoA coupling between filamins unknown","Functional difference between the two N-terminal isoforms not biochemically resolved"]},{"year":2018,"claim":"PKA phosphorylation of Ser2152 was established as a regulatory switch that uncouples FLNA-bound SST2 from Gαi, and single-molecule imaging defined FLNA's role in restraining receptor diffusion and enabling clathrin-mediated internalization.","evidence":"Phosphomimetic/phosphodeficient mutagenesis with functional readouts; fast multicolor single-molecule live imaging with dominant-negative perturbation","pmids":["30098401","29931263"],"confidence":"High","gaps":["Generalizability of Ser2152 regulation to other receptors not tested here","Stoichiometry of FLNA-receptor interactions unknown"]},{"year":2021,"claim":"FLNA was implicated in nuclear DNA repair and cancer drug resistance through TRIM44-mediated stabilization and Wnt/ANXA2 signaling, expanding its roles beyond the cytoskeleton.","evidence":"TRIM44/p62 Co-IP and fractionation with irradiation DNA damage assays; FLNA-ANXA2 Co-IP, SP1 ChIP, and xenografts","pmids":["34211088","34018148"],"confidence":"Medium","gaps":["Direct DNA repair function of nuclear FLNA not biochemically defined","Single-lab Co-IPs without reciprocal structural validation"]},{"year":2023,"claim":"FLNA was shown to function in autophagy by bridging ATG8 proteins to phosphorylated STX17, enabling autophagosome-lysosome fusion, with disease mutations disrupting these interactions.","evidence":"Phospho-site mapping, Co-IP interaction mapping, fusion assays, and disease-mutant constructs","pmids":["37389864"],"confidence":"High","gaps":["Structural basis of ATG8 and STX17 binding regions not resolved","In vivo autophagy phenotype of these mutations not shown here"]},{"year":2024,"claim":"FLNA was assigned cell-cycle and neuronal morphogenesis roles via proteasomal control of Wee1 and an ARHGAP24-RAC1-cofilin axis governing dendritogenesis.","evidence":"FLNA knockdown/overexpression with proteasome inhibitor in carcinoma cells; conditional neuronal Flna depletion with RAC1/cofilin assays","pmids":["39528354","38852754"],"confidence":"Medium","gaps":["Direct mechanism of FLNA-driven Wee1 phosphorylation unclear","ARHGAP24 binding interface on FLNA not mapped"]},{"year":null,"claim":"How a single scaffold coordinates its many partner-specific functions across cytoskeleton, receptor signaling, autophagy, nuclear repair, and cell cycle in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of full-length dimeric FLNA with bound partners","Rules governing partner selection across tissues unknown","Quantitative interplay of phosphorylation and ubiquitination in regulating FLNA function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8,13,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,10,21,23]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,12,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,6,21]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[3,5,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[15,17]}],"complexes":[],"partners":["SYK","PACSIN2","PTPN12","STX17","FLNB","ARHGAP24","TRIM44","ANXA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21333","full_name":"Filamin-A","aliases":["Actin-binding protein 280","ABP-280","Alpha-filamin","Endothelial actin-binding protein","Filamin-1","Non-muscle filamin"],"length_aa":2647,"mass_kda":280.7,"function":"Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNB may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance (By similarity). 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34272929","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49614,"output_tokens":6507,"usd":0.123223,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15538,"output_tokens":4703,"usd":0.097632,"stage2_stop_reason":"end_turn"},"total_usd":0.220855,"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\": 1993,\n      \"finding\": \"The ABP-280 filamin gene (FLN/FLNA) was mapped to Xq28 by Southern blot analysis of somatic cell hybrid lines and fluorescence in situ hybridization, localizing it within a 200-kb region centromeric to G6PD and telomeric to the color vision locus.\",\n      \"method\": \"Southern blot of somatic cell hybrids, FISH\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal mapping methods (somatic cell hybrid Southern blot + FISH), replicated by cosmid/YAC mapping\",\n      \"pmids\": [\"8406501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human FLNA (FLN1) gene comprises 47 exons spanning ~26 kb; the actin-binding domain is encoded by exons 2–5; the 96-amino-acid rod repeats are encoded by the remaining 42 exons; and exon 29 encodes an alternatively spliced 8-amino-acid segment interrupting repeat 15.\",\n      \"method\": \"Genomic cloning and exon-intron sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete gene structure determined by direct sequencing; foundational structural paper\",\n      \"pmids\": [\"8088819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Complete loss of Flna in mice causes embryonic lethality with severe cardiac and vascular defects; Flna-null embryos display abnormal adherens junctions and aberrant endothelial/epithelial organization, demonstrating an essential role for FLNA in intercellular junctions and vascular development rather than in general cell migration.\",\n      \"method\": \"Conditional and complete knockout mouse model; histology; immunostaining of adherens junction markers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype (adherens junction disruption), cardiac/vascular structural readout, multiple tissues examined\",\n      \"pmids\": [\"17172441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FlnA binds to the protein tyrosine kinase Syk at immunoglobulin-like repeat 5 of FlnA; loss of this interaction in FlnA-null platelets severely impairs ITAM- and ITAM-like-mediated signaling (Syk and PLCγ2 phosphorylation), platelet spreading, α-granule secretion, and integrin αIIbβ3 activation.\",\n      \"method\": \"Platelet-specific conditional KO (GATA1-Cre); Co-IP mapping of FlnA–Syk interaction to repeat 5; functional platelet assays (spreading, secretion, tyrosine phosphorylation)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction mapping with domain-level resolution, clean conditional KO with multiple orthogonal functional readouts\",\n      \"pmids\": [\"20713593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FLN-1/filamin in C. elegans is required to maintain actin filament organization in the spermatheca and uterus, and genetic epistasis with phospholipase PLC-1 places both proteins in the same pathway controlling embryo exit from the spermatheca.\",\n      \"method\": \"Deletion allele and RNAi depletion; double-mutant epistasis analysis; fluorescence colocalization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined phenotype plus genetic epistasis, single lab\",\n      \"pmids\": [\"20707996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FlnA-null megakaryocytes prematurely release large, fragile platelets; FlnA stabilizes the platelet von Willebrand factor receptor GPIbα by providing cytoskeletal linkage, as shown by normal GPIbα surface expression on null megakaryocytes but decreased expression and increased ADAM17/MMP9-mediated degradation on null platelets.\",\n      \"method\": \"Megakaryocyte-specific conditional KO (PF4-Cre); flow cytometry; clodronate liposome macrophage ablation; surface receptor expression analysis; western blot for metalloproteinases\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with mechanistic dissection of GPIbα stabilization, multiple orthogonal methods\",\n      \"pmids\": [\"21652675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FLNA overexpression in Tsc1-null neurons is driven by MEK1/2–ERK1/2 signaling (not mTOR), and elevated FLNA causes abnormal dendritic complexity; knockdown of FLNA in Tsc1-null neurons in vivo prevents dendritic abnormalities, placing FLNA downstream of MEK–ERK in the TSC dendritic pathology pathway.\",\n      \"method\": \"In utero electroporation (loss- and gain-of-function); conditional Tsc1-null mouse; MEK inhibitor pharmacology; in vivo FLNA knockdown with phenotypic rescue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic manipulations in vivo with pharmacological confirmation, clean epistasis between MEK-ERK and FLNA\",\n      \"pmids\": [\"25277454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FLNA is required for SST2 (somatostatin receptor 2) signaling and receptor stabilization in somatotroph tumor cells: FLNA silencing abolishes SST2-induced cyclin D1 reduction and caspase-3/7 activation; a FLNA dominant-negative mutant blocking SST2–FLNA binding reduces SST2 expression after prolonged agonist exposure; FLNA also scaffolds Gαi and partner proteins to SST2 to mediate ERK1/2 inhibition and apoptosis.\",\n      \"method\": \"siRNA silencing; dominant-negative FLNA mutant overexpression; caspase activity assay; ERK1/2 phosphorylation assay; cell proliferation assay in human GH-secreting tumor cells and GH3/GH4C1 rat cell lines\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (siRNA + dominant-negative), multiple functional readouts (proliferation, apoptosis, signaling), human and rodent models\",\n      \"pmids\": [\"24828612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FlnA binds PACSIN2 via FlnA immunoglobulin-like repeat 20 interacting with the tip of PACSIN2's F-BAR domain; this interaction enhances PACSIN2 F-BAR-mediated membrane tubulation in vitro and is required for proper demarcation membrane system (DMS) formation and PACSIN2 localization in megakaryocytes and platelets.\",\n      \"method\": \"Co-IP (human platelets); domain-mapping of the FlnA–PACSIN2 interaction; in vitro membrane tubulation assay; Flna-null platelet/MK imaging; EGFP-PACSIN2 localization in wild-type vs Flna-null MKs\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro tubulation assay plus domain-resolved Co-IP, confirmed in null cells with live imaging\",\n      \"pmids\": [\"25838348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MVP-associated FLNA missense mutations (G288R, P637Q, H743P) in repeats 1–8 abolish binding to the tyrosine phosphatase PTPN12 (PTP-PEST), identified by yeast two-hybrid screen, and impair activation of PTPN12 substrates Src and p190RhoGAP, linking FLNA to integrin/focal adhesion signaling via PTPN12.\",\n      \"method\": \"Yeast two-hybrid screen; pull-down; Co-IP; phosphorylation assays for Src and p190RhoGAP\",\n      \"journal\": \"Journal of cardiovascular development and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP and downstream signaling readouts, single lab\",\n      \"pmids\": [\"26594644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FlnA physically interacts with FlnB in chondrocyte cytoplasm; FlnA more strongly binds and activates RhoA whereas FlnB indirectly inhibits RhoA; FlnA loss decreases β1-integrin expression while FlnB loss promotes it, demonstrating antagonistic roles of the two filamins in RhoA activation, integrin expression, actin stress fiber formation, and cell spreading.\",\n      \"method\": \"Co-IP (physical interaction); RhoA activation assay; integrin expression (western blot/flow cytometry); actin staining; fibronectin stimulation in null cells; cell spreading assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multiple functional assays, single lab\",\n      \"pmids\": [\"28175289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two FLNA transcripts differing by 28 N-terminal residues (initiated at ATG+1 and ATG+82) are expressed in a tissue-specific manner; the longer isoform (ATG+1) predominates in intestinal smooth muscle, and mutations that selectively eliminate this isoform cause congenital intestinal pseudo-obstruction (CIPO) without brain or cardiac involvement, mechanistically explaining tissue-specific phenotypes.\",\n      \"method\": \"RNA-seq; cDNA analysis; isoform-specific expression in patient fibroblasts and intestinal smooth muscle; identification of three transcription start sites\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus patient-level isoform analysis with genotype-phenotype correlation, single lab\",\n      \"pmids\": [\"29024177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKA phosphorylates FLNA at S2152 (promoted by cAMP), and SST2 agonist stimulation decreases this phosphorylation; phosphomimetic S2152D FLNA abolishes SST2 antitumoral effects (inhibition of proliferation, apoptosis induction, migration inhibition via RhoA/cofilin), while S2152A FLNA is recruited to activated SST2 normally; S2152D FLNA constitutively binds SST2 but prevents Gαi recruitment, blocking signal transduction.\",\n      \"method\": \"Phosphomimetic/phosphodeficient FLNA mutant overexpression; Co-IP; immunofluorescence; proliferation, apoptosis, and migration assays; RhoA activation assay; cofilin phosphorylation assay in GH3/GH4C1 and primary somatotroph cells\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of specific phosphosite with multiple orthogonal functional readouts, mechanistic dissection of phosphorylation effect on receptor coupling\",\n      \"pmids\": [\"30098401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Single-molecule microscopy shows SSTR2 and FLNA undergo transient interactions preferentially along actin fibers at the plasma membrane; these interactions restrain SSTR2 diffusion, promote agonist-induced SSTR2 clustering and recruitment to clathrin-coated pits, and are required for SSTR2 internalization; a dominant-negative FLNA fragment disrupting SSTR2–FLNA binding increases SSTR2 mobility and impairs clustering and internalization.\",\n      \"method\": \"Fast multicolor single-molecule microscopy in living cells; dominant-negative FLNA fragment; SSTR2 diffusion analysis; clathrin-coated pit recruitment assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule live imaging with dominant-negative perturbation, quantitative mechanistic dissection at nanoscale resolution\",\n      \"pmids\": [\"29931263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A missense mutation (p.Gly2593Glu) in the FLNA repeat 24 dimerization interface abolishes homodimerization of isolated repeat 24 in vitro, but extended repeat 16–24 constructs retain dimerization, implying additional non-canonical interactions contribute to FLNA homodimerization.\",\n      \"method\": \"Co-immunoprecipitation; in vitro cross-linking studies; gel filtration chromatography of repeat 24 and repeat 16–24 constructs\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — three orthogonal in vitro methods (Co-IP, crosslinking, gel filtration) in single study\",\n      \"pmids\": [\"25686753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM44 deubiquitinates p62 (sequestosome 1), promoting its oligomerization and cytoplasmic retention, which prevents p62-mediated nuclear degradation of FLNA and 53BP1, thereby increasing nuclear FLNA levels and DNA damage repair capacity.\",\n      \"method\": \"TRIM44 siRNA knockdown; western blot; subcellular fractionation; irradiation-induced DNA damage assay; co-IP for TRIM44–p62 interaction\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue experiments linking p62 deubiquitination to nuclear FLNA retention, single lab\",\n      \"pmids\": [\"34211088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FLNA interacts with ANXA2 (annexin A2), and together they activate Wnt pathway signaling to promote gefitinib resistance in non-small-cell lung cancer; SP1 transcription factor promotes FLNA transcriptional activation; FLNA knockdown restores gefitinib sensitivity in vitro and in vivo.\",\n      \"method\": \"Co-IP (FLNA–ANXA2 interaction); ChIP (SP1 binding to FLNA promoter); CCK-8/flow cytometry; xenograft mouse model; western blot for Wnt pathway components\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus ChIP for upstream regulation plus in vivo rescue, single lab\",\n      \"pmids\": [\"34018148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM44 interacts with FLNA and facilitates its stability through deubiquitination; FLNA is required for TRIM44-mediated upregulation of BRCA1 expression and homologous recombination repair, placing FLNA upstream of BRCA1 in a TRIM44/FLNA/BRCA1 axis that confers cisplatin resistance in lung adenocarcinoma.\",\n      \"method\": \"Co-IP (TRIM44–FLNA interaction); FLNA siRNA; BRCA1 depletion rescue experiment; immunofluorescence; xenograft model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus epistatic rescue experiment (BRCA1 depletion reverses TRIM44 effect), single lab\",\n      \"pmids\": [\"35541909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ULK kinase phosphorylates the autophagosomal SNARE STX17 at S289; FLNA acts as a linker between ATG8 family proteins and STX17, recruiting STX17 to autophagosomes; STX17 S289 phosphorylation promotes interaction with FLNA, enabling STX17 recruitment to autophagosomes and facilitating autophagosome–lysosome fusion; disease-causative FLNA mutations in the ATG8- and STX17-binding regions disrupt these interactions and impair fusion.\",\n      \"method\": \"Phospho-site mapping (ULK→STX17 S289); Co-IP (FLNA–ATG8, FLNA–STX17); autophagosome–lysosome fusion assay; disease-mutant FLNA constructs; subcellular localization studies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phospho-site mutagenesis combined with Co-IP interaction mapping and functional fusion assay, with disease-mutation validation\",\n      \"pmids\": [\"37389864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WTAP-mediated N6-methyladenosine (m6A) modification of FLNA mRNA leads to post-transcriptional repression of FLNA expression, and the WTAP/FLNA axis inhibits autophagy in colon cancer cells.\",\n      \"method\": \"m6A dot blot hybridization; methylated RNA immunoprecipitation (MeRIP); dual-luciferase assay; RNA immunoprecipitation; western blot for FLNA and autophagy markers; rescue experiments\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA-modification assays (MeRIP, RIP) plus functional rescue, single lab\",\n      \"pmids\": [\"36849408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLNA regulates Wee1 kinase protein levels by promoting its proteasomal degradation (via phosphorylation at Ser123); FLNA knockdown increases Wee1 and p-CDK1/cyclin B1 whereas FLNA overexpression increases p-Wee1(Ser123) and reduces Wee1 protein, reversed by lactacystin (proteasome inhibitor), placing FLNA as a negative regulator of Wee1 in adrenocortical carcinoma cells.\",\n      \"method\": \"FLNA knockdown and overexpression; western blot for Wee1, p-CDK1, cyclin B1, p-Wee1(Ser123); lactacystin proteasome inhibitor treatment; proliferation and apoptosis assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic evidence for proteasome-dependent Wee1 degradation regulated by FLNA, single lab\",\n      \"pmids\": [\"39528354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein ARHGAP24, regulating dendritogenesis and spinogenesis in cortical pyramidal neurons; conditional Flna depletion from pyramidal neurons disrupts excitatory/inhibitory input balance.\",\n      \"method\": \"Conditional in utero electroporation of Cre in Flnaflox/flox mice; RAC1 activation assay; cofilin phosphorylation assay; Co-IP or interaction assay for FLNA–ARHGAP24; dendritic morphology quantification\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional neuronal KO with specific molecular mechanism (ARHGAP24–RAC1–cofilin axis), single lab\",\n      \"pmids\": [\"38852754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A loss-of-function FLNA mutation inducing in-frame exon 40 skipping produces a mutant FLNA missing 41 internal amino acids that retains binding affinity to integrin and capacity to induce focal adhesions comparable to wild-type protein, demonstrating that this internal region is dispensable for integrin binding and focal adhesion formation.\",\n      \"method\": \"Whole-exome sequencing; RT-PCR/cDNA characterization of exon skipping; functional assay of integrin binding and focal adhesion formation for mutant vs wild-type FLNA\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay of mutant protein (integrin binding + focal adhesion), single study\",\n      \"pmids\": [\"26059841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLNA colocalizes with Rap1-GTPase in cellular protrusions of pulmonary neuroendocrine tumor cells; FLNA silencing up-regulates Rap1 expression, and Rap1 silencing prevents the FLNA-silencing-induced increase in cell adhesion and decrease in cell migration, placing Rap1 downstream of FLNA in the regulation of these processes.\",\n      \"method\": \"siRNA silencing; immunofluorescence colocalization; Rap1 western blot; cell adhesion and migration assays; epistasis via double knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic double-knockdown plus colocalization, single lab\",\n      \"pmids\": [\"29100390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FLNA directly interacts with Smad2, enhancing c-Met promoter activity; c-Met–AKT signaling phosphorylates FLNA at Ser2152, and this phosphorylation is correlated with EMT; co-immunoprecipitation confirmed FLNA–Smad2 interaction; FLNA knockdown reduces EMT and metastasis in colorectal cancer cells in vivo.\",\n      \"method\": \"Co-immunoprecipitation (FLNA–Smad2); luciferase reporter assay (c-Met promoter); orthotopic CRC mouse model; western blot for EMT markers and pFLNA(Ser2152)\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus luciferase reporter plus in vivo model, single lab\",\n      \"pmids\": [\"32195017\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FLNA encodes a large dimeric actin-crosslinking scaffold protein that physically links transmembrane receptors (GPIbα, integrins, SST2/SSTR2) to the actin cytoskeleton via its 24 immunoglobulin-like repeats, and serves as a signaling hub by recruiting and regulating kinases (Syk, RhoA, RAC1–cofilin via ARHGAP24), phosphatases (PTPN12), and G-proteins (Gαi, Rap1); its scaffold function is regulated by PKA-mediated phosphorylation at Ser2152 and by TRIM44-mediated deubiquitination (affecting nuclear levels and DNA repair), while it also participates in autophagosome maturation by bridging ATG8 proteins to STX17 to enable autophagosome–lysosome fusion; loss-of-function disrupts adherens junctions, neuronal migration, platelet biogenesis and ITAM signaling, smooth muscle layering, and dendritic morphogenesis, whereas gain-of-function missense mutations cause skeletal dysplasias, collectively explaining the broad developmental and signaling roles of this protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FLNA encodes a large dimeric actin-crosslinking scaffold built from an N-terminal actin-binding domain and 24 immunoglobulin-like repeats, whose homodimerization is mediated by repeat 24 together with additional non-canonical contacts within repeats 16\\u201324 [#1, #14]. It is essential for the integrity of intercellular junctions and vascular/cardiac development, with complete loss in mice causing embryonic lethality and disrupted adherens junctions [#2]. The protein operates as a signaling hub that physically links transmembrane receptors to the actin cytoskeleton and the Rho-GTPase machinery: it binds the tyrosine kinase Syk at repeat 5 to drive ITAM-mediated platelet activation [#3], stabilizes the GPIb\\u03b1 receptor against ADAM17/MMP9-mediated proteolysis during platelet biogenesis [#5], and tethers the F-BAR protein PACSIN2 via repeat 20 to shape the megakaryocyte demarcation membrane system [#8]. Through differential coupling to RhoA and \\u03b21-integrin it acts antagonistically to FLNB in controlling stress fibers and cell spreading [#10], and it directs cytoskeletal remodeling via PTPN12/Src/p190RhoGAP [#9], Rap1 [#23], and an ARHGAP24\\u2013RAC1\\u2013cofilin axis governing dendritogenesis [#21]. FLNA scaffolds somatostatin receptor SST2/SSTR2 signaling, restraining receptor diffusion and clustering at clathrin-coated pits to enable internalization and G\\u03b1i-coupled antitumoral signaling, a function gated by PKA phosphorylation at Ser2152 that uncouples G\\u03b1i recruitment [#12, #13]. It additionally bridges ATG8-family proteins to the SNARE STX17 to promote autophagosome\\u2013lysosome fusion [#18]. FLNA mutations cause tissue-specific developmental disease, including isoform-specific congenital intestinal pseudo-obstruction [#11], and elevated FLNA downstream of MEK\\u2013ERK drives dendritic pathology in Tsc1-null neurons [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the gene's domain architecture defined FLNA as a modular actin-binding protein, framing all later structure-function work.\",\n      \"evidence\": \"Genomic cloning and exon-intron sequencing of the 47-exon human gene\",\n      \"pmids\": [\"8088819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address dimerization geometry\", \"No functional assignment to individual repeats\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether FLNA's essential role lay in cell migration or junction integrity was resolved by showing null embryos die with adherens junction and vascular defects, redefining its core developmental function.\",\n      \"evidence\": \"Complete and conditional knockout mouse with histology and adherens junction immunostaining\",\n      \"pmids\": [\"17172441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners at the junction not identified\", \"Tissue-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Domain-resolved interaction mapping established FLNA as a direct signaling scaffold, linking Syk binding at repeat 5 to ITAM-driven platelet activation.\",\n      \"evidence\": \"Platelet-specific conditional KO with reciprocal Co-IP domain mapping and functional platelet assays\",\n      \"pmids\": [\"20713593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other repeats bind additional kinases not addressed in this study\", \"Structural basis of the repeat 5 interface unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The mechanism of FLNA-dependent platelet biogenesis was clarified by showing FLNA stabilizes surface GPIb\\u03b1 against metalloprotease cleavage, explaining the macrothrombocytopenia phenotype.\",\n      \"evidence\": \"Megakaryocyte-specific conditional KO with flow cytometry, macrophage ablation, and metalloproteinase westerns\",\n      \"pmids\": [\"21652675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GPIb\\u03b1-FLNA binding interface not mapped here\", \"Link to premature platelet release not fully mechanistic\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"FLNA was shown to extend cytoskeletal scaffolding to membrane morphogenesis by tethering PACSIN2 at repeat 20 to drive demarcation membrane system formation.\",\n      \"evidence\": \"Co-IP domain mapping, in vitro membrane tubulation assay, and Flna-null megakaryocyte imaging\",\n      \"pmids\": [\"25838348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for DMS in thrombopoiesis not quantified\", \"Regulation of the interaction unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Dimerization studies revealed that repeat 24 alone is insufficient for stable homodimerization, implying non-canonical inter-repeat contacts beyond the canonical interface.\",\n      \"evidence\": \"Co-IP, in vitro cross-linking, and gel filtration of repeat 24 and repeat 16\\u201324 constructs\",\n      \"pmids\": [\"25686753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the additional dimerization contacts not defined\", \"No full-length structural model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A focal-adhesion-competent exon-40-skipping mutant defined an internal region dispensable for integrin binding, refining the structure-function map.\",\n      \"evidence\": \"Whole-exome sequencing, cDNA characterization, and integrin binding/focal adhesion assays\",\n      \"pmids\": [\"26059841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences in tissue context untested\", \"Other functions of the deleted region not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"FLNA was placed in receptor signaling pathways: as a scaffold required for SST2 receptor stabilization and G\\u03b1i-mediated antitumoral signaling, and as a MEK-ERK effector in TSC dendritic pathology.\",\n      \"evidence\": \"siRNA and dominant-negative FLNA in tumor cells; in utero electroporation with MEK inhibitor pharmacology in Tsc1-null neurons\",\n      \"pmids\": [\"24828612\", \"25277454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of receptor scaffolding beyond SST2 unclear\", \"Transcriptional vs post-translational control of FLNA levels in neurons not fully separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Yeast two-hybrid and signaling assays connected disease-associated repeat 1\\u20138 mutations to loss of PTPN12 binding and dysregulated Src/p190RhoGAP, linking FLNA to focal adhesion signaling.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, Co-IP, and Src/p190RhoGAP phosphorylation assays\",\n      \"pmids\": [\"26594644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction not reciprocally validated in vivo\", \"Causality for MVP phenotype not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"FLNA was shown to act antagonistically to FLNB in RhoA activation and integrin expression, and tissue-specific isoforms were linked to organ-restricted disease.\",\n      \"evidence\": \"Co-IP and RhoA/integrin functional assays in chondrocytes; RNA-seq isoform analysis with CIPO genotype-phenotype correlation\",\n      \"pmids\": [\"28175289\", \"29024177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of differential RhoA coupling between filamins unknown\", \"Functional difference between the two N-terminal isoforms not biochemically resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PKA phosphorylation of Ser2152 was established as a regulatory switch that uncouples FLNA-bound SST2 from G\\u03b1i, and single-molecule imaging defined FLNA's role in restraining receptor diffusion and enabling clathrin-mediated internalization.\",\n      \"evidence\": \"Phosphomimetic/phosphodeficient mutagenesis with functional readouts; fast multicolor single-molecule live imaging with dominant-negative perturbation\",\n      \"pmids\": [\"30098401\", \"29931263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of Ser2152 regulation to other receptors not tested here\", \"Stoichiometry of FLNA-receptor interactions unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"FLNA was implicated in nuclear DNA repair and cancer drug resistance through TRIM44-mediated stabilization and Wnt/ANXA2 signaling, expanding its roles beyond the cytoskeleton.\",\n      \"evidence\": \"TRIM44/p62 Co-IP and fractionation with irradiation DNA damage assays; FLNA-ANXA2 Co-IP, SP1 ChIP, and xenografts\",\n      \"pmids\": [\"34211088\", \"34018148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA repair function of nuclear FLNA not biochemically defined\", \"Single-lab Co-IPs without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"FLNA was shown to function in autophagy by bridging ATG8 proteins to phosphorylated STX17, enabling autophagosome-lysosome fusion, with disease mutations disrupting these interactions.\",\n      \"evidence\": \"Phospho-site mapping, Co-IP interaction mapping, fusion assays, and disease-mutant constructs\",\n      \"pmids\": [\"37389864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ATG8 and STX17 binding regions not resolved\", \"In vivo autophagy phenotype of these mutations not shown here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"FLNA was assigned cell-cycle and neuronal morphogenesis roles via proteasomal control of Wee1 and an ARHGAP24-RAC1-cofilin axis governing dendritogenesis.\",\n      \"evidence\": \"FLNA knockdown/overexpression with proteasome inhibitor in carcinoma cells; conditional neuronal Flna depletion with RAC1/cofilin assays\",\n      \"pmids\": [\"39528354\", \"38852754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of FLNA-driven Wee1 phosphorylation unclear\", \"ARHGAP24 binding interface on FLNA not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold coordinates its many partner-specific functions across cytoskeleton, receptor signaling, autophagy, nuclear repair, and cell cycle in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of full-length dimeric FLNA with bound partners\", \"Rules governing partner selection across tissues unknown\", \"Quantitative interplay of phosphorylation and ubiquitination in regulating FLNA function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8, 13, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 10, 21, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 12, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 6, 21]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3, 5, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [15, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SYK\", \"PACSIN2\", \"PTPN12\", \"STX17\", \"FLNB\", \"ARHGAP24\", \"TRIM44\", \"ANXA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}