{"gene":"FILIP1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2002,"finding":"FILIP1 interacts with Filamin A (an actin-binding protein required for cell motility) and induces its degradation in COS-7 cells; this FILIP–FilaminA–F-actin axis controls the start of neocortical cell migration from the ventricular zone, where filip mRNA is specifically localized.","method":"Co-immunoprecipitation/interaction assay, overexpression in COS-7 cells, cortical explant migration assay, in situ hybridization","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction demonstrated, functional consequence (failed migration on FILIP overexpression) confirmed in explants, replicated in subsequent papers","pmids":["12055638"],"is_preprint":false},{"year":2004,"finding":"FILIP1-mediated degradation of Filamin A controls the amount of Filamin A in migrating neocortical neurons, determining whether they adopt a multipolar or bipolar shape in the subventricular and intermediate zones; siRNA knockdown of FILIP1 (increasing Filamin A) promotes bipolar morphology and motility.","method":"siRNA knockdown of FILIP1 in cortical neurons, dominant-negative Filamin A expression, in vivo and ex vivo migration assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined cellular phenotype (polarity and motility), corroborated by complementary gain-of-function experiment","pmids":["15509752"],"is_preprint":false},{"year":2014,"finding":"FILIP1 binds near the ATPase domain of non-muscle myosin heavy chain IIb (a component of myosin 2b), interferes with its actin-binding activity, alters the subcellular distribution of myosin 2b in dendritic spines, and modifies NMDA receptor subunit distribution; FILIP1 knockout mice show altered excitation propagation.","method":"Co-immunoprecipitation, actin-binding interference assay, immunofluorescence, FILIP1-knockout mouse electrophysiology","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — binding partner identified, functional modulation of actin-binding demonstrated, confirmed in KO mice; single lab","pmids":["25220605"],"is_preprint":false},{"year":2017,"finding":"FILIP1 interacts with the chaperone Hsc70 via a domain distinct from its myosin IIb-binding domain; this interaction is controlled by Hsc70 ATPase activity and is required for FILIP1 to regulate the subcellular distribution of myosin IIb and spine morphology in primary neurons.","method":"Pull-down assay, mass spectrometry identification of Hsc70, ATPase inhibitor experiments, primary neuron morphology assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — binding partner identified by pulldown + MS, functional consequence (myosin IIb redistribution, spine morphology) demonstrated with inhibitors; single lab","pmids":["28234934"],"is_preprint":false},{"year":2018,"finding":"FILIP1 expression is regulated in cis by the lncRNA Myolinc; knockdown of FILIP1 inhibits myogenic differentiation (reduced myogenic regulatory factor expression and multi-nucleated myotube formation), placing FILIP1 downstream of Myolinc in a myogenesis regulatory axis.","method":"siRNA knockdown of FILIP1 in C2C12 myoblasts, qRT-PCR, immunofluorescence, myotube formation assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific differentiation phenotype; single lab but multiple readouts","pmids":["29618024"],"is_preprint":false},{"year":2020,"finding":"FILIP1 directly binds to Filamin C (FLNc) and induces its degradation; dual-site phosphorylation of FLNc at Ser2234 (by Akt) and a second site (by PKCα) within an extended basophilic motif in Ig-like domain 20 reduces FILIP1 binding, thereby shielding FLNc from FILIP1-mediated degradation and enabling its signaling adaptor function.","method":"Proximity proteomics (BioID), co-immunoprecipitation, quantitative phosphoproteomics, kinase inhibitor experiments, mutagenesis","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 — interaction confirmed by proximity proteomics and Co-IP, phosphorylation sites identified by quantitative phosphoproteomics, mechanistic model validated by mutagenesis and kinase inhibitors","pmids":["32444788"],"is_preprint":false},{"year":2023,"finding":"During myogenic differentiation, FILIP1 localizes first to microtubules (colocalizing with EB3) and then transitions to myofibrillar Z-discs with FLNc; electrical pulse stimulation-induced myofibril lesions cause translocation of FILIP1 and FLNc from Z-discs to lesion sites, implicating FILIP1 as a cytolinker bridging actin filaments and microtubules in myofibril assembly and mechanical stress response.","method":"Immunofluorescence microscopy of differentiating myotubes, electrical pulse stimulation, nocodazole treatment, colocalization analysis","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional context (lesion formation/repair), inhibitor perturbation; single lab","pmids":["37178194"],"is_preprint":false},{"year":2024,"finding":"Protein phosphatase 1 (PP1) — all three isoforms present in the FLNc domain 18–21 interactome — dephosphorylates FLNc at Ser2234 in cultured skeletal myotubes under acute mechanical stress; this dephosphorylation promotes FILIP1 binding to FLNc, linking mechanical stress signaling to FILIP1-dependent filamin degradation.","method":"Quantitative phosphoproteomics, co-immunoprecipitation (FLNc d18-21 interactome), in vitro enzymatic phosphatase assay, PP1 modulator treatments in cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic assay demonstrates PP1 dephosphorylates FLNc-pS2234 in vitro, interactome confirmed by MS, functional consequence (FILIP1 binding) validated in cells","pmids":["39521905"],"is_preprint":false}],"current_model":"FILIP1 is a multifunctional adaptor protein that promotes degradation of filamins (A and C) by binding them directly and facilitating their ubiquitin-proteasome-mediated turnover; in neurons this regulates actin cytoskeleton dynamics, cortical radial migration, and spine morphology (partly via Hsc70-dependent control of myosin IIb), while in skeletal muscle the FILIP1–FLNc interaction is gated by a PP1/Akt phosphorylation switch on FLNc Ser2234 that protects FLNc from FILIP1-induced degradation under steady-state conditions but allows degradation upon mechanical stress-triggered dephosphorylation."},"narrative":{"teleology":[{"year":2002,"claim":"The question of how Filamin A abundance is controlled in migrating neurons was answered by the discovery that FILIP1 binds Filamin A and induces its degradation, establishing FILIP1 as a regulator of the actin cytoskeleton during neocortical migration.","evidence":"Co-immunoprecipitation in COS-7 cells and cortical explant migration assays","pmids":["12055638"],"confidence":"High","gaps":["Proteolytic pathway mediating FILIP1-induced Filamin A degradation not identified","Whether FILIP1 acts on other filamins unknown","In vivo loss-of-function phenotype not yet established"]},{"year":2004,"claim":"The cell-biological consequence of FILIP1-mediated Filamin A control was resolved: FILIP1 determines whether migrating cortical neurons adopt multipolar versus bipolar morphology by titrating Filamin A levels, establishing that FILIP1 is a polarity switch during cortical development.","evidence":"siRNA knockdown of FILIP1 in cortical neurons combined with dominant-negative Filamin A and in vivo migration assays","pmids":["15509752"],"confidence":"High","gaps":["Upstream signals controlling FILIP1 expression in cortical neurons not identified","Whether FILIP1 function is required postnatally unknown"]},{"year":2014,"claim":"Beyond filamins, FILIP1 was shown to bind non-muscle myosin heavy chain IIb near its ATPase domain and modulate its actin-binding activity, establishing a second cytoskeletal target and linking FILIP1 to dendritic spine morphology and neural excitation.","evidence":"Co-immunoprecipitation, actin-binding interference assay, and FILIP1-knockout mouse electrophysiology","pmids":["25220605"],"confidence":"Medium","gaps":["Single lab; independent replication of myosin IIb interaction needed","Structural basis of FILIP1–myosin IIb binding unresolved","Whether FILIP1 degrades myosin IIb or only redistributes it not determined"]},{"year":2017,"claim":"The mechanism by which FILIP1 controls myosin IIb distribution was extended by identifying Hsc70 as a required co-factor: Hsc70 binds FILIP1 via a domain distinct from the myosin IIb-binding region, and its ATPase activity is necessary for FILIP1-dependent regulation of spine morphology.","evidence":"Pull-down with mass spectrometry identification of Hsc70, ATPase inhibitor experiments in primary neurons","pmids":["28234934"],"confidence":"Medium","gaps":["Direct structural or reconstituted biochemical evidence for a tripartite FILIP1–Hsc70–myosin IIb complex lacking","Whether Hsc70 is also involved in FILIP1-mediated filamin degradation untested"]},{"year":2018,"claim":"FILIP1 was placed in a myogenesis regulatory pathway: its expression is controlled by the lncRNA Myolinc, and FILIP1 knockdown impairs myogenic differentiation, revealing a muscle-specific function beyond the neuronal context.","evidence":"siRNA knockdown of FILIP1 in C2C12 myoblasts with qRT-PCR and myotube formation assays","pmids":["29618024"],"confidence":"Medium","gaps":["Whether the myogenesis role operates through filamin degradation or an independent mechanism not determined","In vivo muscle phenotype of FILIP1 loss not reported"]},{"year":2020,"claim":"The question of how FILIP1-mediated filamin degradation is regulated was answered: dual phosphorylation of FLNc Ser2234 (by Akt) and a second site (by PKCα) shields FLNc from FILIP1 binding, establishing a phosphorylation-dependent gating mechanism for FILIP1 activity in muscle.","evidence":"BioID proximity proteomics, quantitative phosphoproteomics, kinase inhibitor experiments, and phosphosite mutagenesis","pmids":["32444788"],"confidence":"High","gaps":["Identity of the E3 ligase mediating FILIP1-dependent FLNc proteasomal degradation unknown","Whether the same phospho-switch regulates FILIP1 binding to Filamin A untested"]},{"year":2023,"claim":"FILIP1's dynamic localization during myogenesis was mapped — it transitions from microtubules (EB3-positive) to Z-discs with FLNc, and both proteins relocate to myofibrillar lesion sites under mechanical stress, establishing FILIP1 as a cytolinker involved in myofibril assembly and damage response.","evidence":"Immunofluorescence in differentiating myotubes with electrical pulse stimulation and nocodazole treatment","pmids":["37178194"],"confidence":"Medium","gaps":["Direct microtubule-binding domain in FILIP1 not mapped","Whether FILIP1 promotes repair or degradation at lesion sites not distinguished","Single lab observation"]},{"year":2024,"claim":"The upstream phosphatase completing the FLNc phospho-switch was identified: PP1 dephosphorylates FLNc Ser2234 under acute mechanical stress, promoting FILIP1 binding and thus coupling mechanical damage sensing to FILIP1-dependent filamin degradation.","evidence":"In vitro phosphatase assay, quantitative phosphoproteomics, and PP1 modulator treatments in skeletal myotubes","pmids":["39521905"],"confidence":"High","gaps":["Mechanosensor upstream of PP1 activation not identified","Whether PP1-FILIP1 axis operates in non-muscle contexts unknown","In vivo validation of PP1-FLNc-FILIP1 axis in muscle injury models lacking"]},{"year":null,"claim":"The E3 ubiquitin ligase that mediates FILIP1-dependent filamin degradation has not been identified, and the structural basis of FILIP1 binding to its multiple cytoskeletal partners (Filamin A, Filamin C, myosin IIb, EB3/microtubules) remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No E3 ligase identified for FILIP1-induced proteasomal degradation of filamins","No structural model for any FILIP1 interaction","In vivo muscle phenotype of FILIP1 loss-of-function not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,7]}],"complexes":[],"partners":["FLNA","FLNC","MYH10","HSPA8","PPP1CA"],"other_free_text":[]},"mechanistic_narrative":"FILIP1 is a cytoskeletal adaptor protein that controls filamin turnover and actomyosin organization in both neurons and skeletal muscle. FILIP1 directly binds Filamin A and Filamin C and promotes their degradation; in developing neocortex this regulates the Filamin A pool to govern cortical neuron polarity and radial migration, while in skeletal muscle the FILIP1–FLNc interaction is gated by Akt/PKCα phosphorylation of FLNc Ser2234, which is reversed by PP1 under mechanical stress to permit FILIP1-dependent FLNc degradation [PMID:12055638, PMID:32444788, PMID:39521905]. FILIP1 also binds the ATPase domain of non-muscle myosin heavy chain IIb in an Hsc70-dependent manner, regulating myosin IIb subcellular distribution and dendritic spine morphology [PMID:25220605, PMID:28234934]. During myogenic differentiation, FILIP1 transitions from microtubule association (with EB3) to Z-disc localization with FLNc and is recruited to myofibrillar lesion sites upon mechanical stress, functioning as a cytolinker that bridges actin filaments and microtubules during myofibril assembly and repair [PMID:37178194, PMID:29618024]."},"prefetch_data":{"uniprot":{"accession":"Q7Z7B0","full_name":"Filamin-A-interacting protein 1","aliases":[],"length_aa":1213,"mass_kda":138.1,"function":"By acting through a filamin-A/F-actin axis, it controls the start of neocortical cell migration from the ventricular zone. May be able to induce the degradation of filamin-A","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q7Z7B0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FILIP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FILIP1","total_profiled":1310},"omim":[{"mim_id":"620775","title":"NEUROMUSCULAR DISORDER, CONGENITAL, WITH DYSMORPHIC FACIES; NMDF","url":"https://www.omim.org/entry/620775"},{"mim_id":"612993","title":"FILAMIN A-INTERACTING PROTEIN 1-LIKE; FILIP1L","url":"https://www.omim.org/entry/612993"},{"mim_id":"607307","title":"FILAMIN A-INTERACTING PROTEIN 1; FILIP1","url":"https://www.omim.org/entry/607307"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":50.3},{"tissue":"skeletal muscle","ntpm":33.8},{"tissue":"tongue","ntpm":45.6}],"url":"https://www.proteinatlas.org/search/FILIP1"},"hgnc":{"alias_symbol":["FILIP","KIAA1275"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z7B0","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7B0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7B0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z7B0-F1-predicted_aligned_error_v6.png","plddt_mean":66.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FILIP1","jax_strain_url":"https://www.jax.org/strain/search?query=FILIP1"},"sequence":{"accession":"Q7Z7B0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z7B0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z7B0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z7B0"}},"corpus_meta":[{"pmid":"12055638","id":"PMC_12055638","title":"Filamin A-interacting protein (FILIP) regulates cortical cell migration out of the ventricular zone.","date":"2002","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12055638","citation_count":113,"is_preprint":false},{"pmid":"15509752","id":"PMC_15509752","title":"Filamin A and FILIP (Filamin A-Interacting Protein) regulate cell polarity and motility in neocortical subventricular and intermediate zones during radial migration.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15509752","citation_count":113,"is_preprint":false},{"pmid":"29618024","id":"PMC_29618024","title":"A novel long non-coding RNA Myolinc regulates myogenesis through TDP-43 and Filip1.","date":"2018","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29618024","citation_count":59,"is_preprint":false},{"pmid":"21784850","id":"PMC_21784850","title":"Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A-interacting protein 1-like (FILIP-1L).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21784850","citation_count":33,"is_preprint":false},{"pmid":"32444788","id":"PMC_32444788","title":"Phosphoproteomics identifies dual-site phosphorylation in an extended basophilic motif regulating FILIP1-mediated degradation of filamin-C.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32444788","citation_count":33,"is_preprint":false},{"pmid":"15794127","id":"PMC_15794127","title":"Involvement of filamin A and filamin A-interacting protein (FILIP) in controlling the start and cell shape of radially migrating cortical neurons.","date":"2005","source":"Anatomical science international","url":"https://pubmed.ncbi.nlm.nih.gov/15794127","citation_count":27,"is_preprint":false},{"pmid":"25220605","id":"PMC_25220605","title":"Filamin A-interacting protein (FILIP) is a region-specific modulator of myosin 2b and controls spine morphology and NMDA receptor accumulation.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25220605","citation_count":10,"is_preprint":false},{"pmid":"37163662","id":"PMC_37163662","title":"Bi-allelic variants of FILIP1 cause congenital myopathy, dysmorphism and neurological defects.","date":"2023","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37163662","citation_count":8,"is_preprint":false},{"pmid":"37178194","id":"PMC_37178194","title":"Filamin-A-interacting protein 1 (FILIP1) is a dual compartment protein linking myofibrils and microtubules during myogenic differentiation and upon mechanical stress.","date":"2023","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/37178194","citation_count":7,"is_preprint":false},{"pmid":"28234934","id":"PMC_28234934","title":"Subcellular distribution of non-muscle myosin IIb is controlled by FILIP through Hsc70.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28234934","citation_count":6,"is_preprint":false},{"pmid":"39521905","id":"PMC_39521905","title":"Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39521905","citation_count":3,"is_preprint":false},{"pmid":"36943452","id":"PMC_36943452","title":"Homozygous loss-of-function variants in FILIP1 cause autosomal recessive arthrogryposis multiplex congenita with microcephaly.","date":"2023","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36943452","citation_count":3,"is_preprint":false},{"pmid":"23277876","id":"PMC_23277876","title":"Association Analysis Between FILIP1 Polymorphisms and Aspirin Hypersensitivity in Korean Asthmatics.","date":"2012","source":"Allergy, asthma & immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/23277876","citation_count":2,"is_preprint":false},{"pmid":"39961470","id":"PMC_39961470","title":"Deletion of filamin A-interacting protein (FILIP) results in a weak grip strength and abnormal responses to nociceptive stimulation.","date":"2025","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/39961470","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7636,"output_tokens":2102,"usd":0.027219},"stage2":{"model":"claude-opus-4-6","input_tokens":5401,"output_tokens":2489,"usd":0.133845},"total_usd":0.161064,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"FILIP1 interacts with Filamin A (an actin-binding protein required for cell motility) and induces its degradation in COS-7 cells; this FILIP–FilaminA–F-actin axis controls the start of neocortical cell migration from the ventricular zone, where filip mRNA is specifically localized.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay, overexpression in COS-7 cells, cortical explant migration assay, in situ hybridization\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction demonstrated, functional consequence (failed migration on FILIP overexpression) confirmed in explants, replicated in subsequent papers\",\n      \"pmids\": [\"12055638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FILIP1-mediated degradation of Filamin A controls the amount of Filamin A in migrating neocortical neurons, determining whether they adopt a multipolar or bipolar shape in the subventricular and intermediate zones; siRNA knockdown of FILIP1 (increasing Filamin A) promotes bipolar morphology and motility.\",\n      \"method\": \"siRNA knockdown of FILIP1 in cortical neurons, dominant-negative Filamin A expression, in vivo and ex vivo migration assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype (polarity and motility), corroborated by complementary gain-of-function experiment\",\n      \"pmids\": [\"15509752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FILIP1 binds near the ATPase domain of non-muscle myosin heavy chain IIb (a component of myosin 2b), interferes with its actin-binding activity, alters the subcellular distribution of myosin 2b in dendritic spines, and modifies NMDA receptor subunit distribution; FILIP1 knockout mice show altered excitation propagation.\",\n      \"method\": \"Co-immunoprecipitation, actin-binding interference assay, immunofluorescence, FILIP1-knockout mouse electrophysiology\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding partner identified, functional modulation of actin-binding demonstrated, confirmed in KO mice; single lab\",\n      \"pmids\": [\"25220605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FILIP1 interacts with the chaperone Hsc70 via a domain distinct from its myosin IIb-binding domain; this interaction is controlled by Hsc70 ATPase activity and is required for FILIP1 to regulate the subcellular distribution of myosin IIb and spine morphology in primary neurons.\",\n      \"method\": \"Pull-down assay, mass spectrometry identification of Hsc70, ATPase inhibitor experiments, primary neuron morphology assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — binding partner identified by pulldown + MS, functional consequence (myosin IIb redistribution, spine morphology) demonstrated with inhibitors; single lab\",\n      \"pmids\": [\"28234934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FILIP1 expression is regulated in cis by the lncRNA Myolinc; knockdown of FILIP1 inhibits myogenic differentiation (reduced myogenic regulatory factor expression and multi-nucleated myotube formation), placing FILIP1 downstream of Myolinc in a myogenesis regulatory axis.\",\n      \"method\": \"siRNA knockdown of FILIP1 in C2C12 myoblasts, qRT-PCR, immunofluorescence, myotube formation assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific differentiation phenotype; single lab but multiple readouts\",\n      \"pmids\": [\"29618024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FILIP1 directly binds to Filamin C (FLNc) and induces its degradation; dual-site phosphorylation of FLNc at Ser2234 (by Akt) and a second site (by PKCα) within an extended basophilic motif in Ig-like domain 20 reduces FILIP1 binding, thereby shielding FLNc from FILIP1-mediated degradation and enabling its signaling adaptor function.\",\n      \"method\": \"Proximity proteomics (BioID), co-immunoprecipitation, quantitative phosphoproteomics, kinase inhibitor experiments, mutagenesis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — interaction confirmed by proximity proteomics and Co-IP, phosphorylation sites identified by quantitative phosphoproteomics, mechanistic model validated by mutagenesis and kinase inhibitors\",\n      \"pmids\": [\"32444788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During myogenic differentiation, FILIP1 localizes first to microtubules (colocalizing with EB3) and then transitions to myofibrillar Z-discs with FLNc; electrical pulse stimulation-induced myofibril lesions cause translocation of FILIP1 and FLNc from Z-discs to lesion sites, implicating FILIP1 as a cytolinker bridging actin filaments and microtubules in myofibril assembly and mechanical stress response.\",\n      \"method\": \"Immunofluorescence microscopy of differentiating myotubes, electrical pulse stimulation, nocodazole treatment, colocalization analysis\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional context (lesion formation/repair), inhibitor perturbation; single lab\",\n      \"pmids\": [\"37178194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Protein phosphatase 1 (PP1) — all three isoforms present in the FLNc domain 18–21 interactome — dephosphorylates FLNc at Ser2234 in cultured skeletal myotubes under acute mechanical stress; this dephosphorylation promotes FILIP1 binding to FLNc, linking mechanical stress signaling to FILIP1-dependent filamin degradation.\",\n      \"method\": \"Quantitative phosphoproteomics, co-immunoprecipitation (FLNc d18-21 interactome), in vitro enzymatic phosphatase assay, PP1 modulator treatments in cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic assay demonstrates PP1 dephosphorylates FLNc-pS2234 in vitro, interactome confirmed by MS, functional consequence (FILIP1 binding) validated in cells\",\n      \"pmids\": [\"39521905\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FILIP1 is a multifunctional adaptor protein that promotes degradation of filamins (A and C) by binding them directly and facilitating their ubiquitin-proteasome-mediated turnover; in neurons this regulates actin cytoskeleton dynamics, cortical radial migration, and spine morphology (partly via Hsc70-dependent control of myosin IIb), while in skeletal muscle the FILIP1–FLNc interaction is gated by a PP1/Akt phosphorylation switch on FLNc Ser2234 that protects FLNc from FILIP1-induced degradation under steady-state conditions but allows degradation upon mechanical stress-triggered dephosphorylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FILIP1 is a cytoskeletal adaptor protein that controls filamin turnover and actomyosin organization in both neurons and skeletal muscle. FILIP1 directly binds Filamin A and Filamin C and promotes their degradation; in developing neocortex this regulates the Filamin A pool to govern cortical neuron polarity and radial migration, while in skeletal muscle the FILIP1–FLNc interaction is gated by Akt/PKCα phosphorylation of FLNc Ser2234, which is reversed by PP1 under mechanical stress to permit FILIP1-dependent FLNc degradation [PMID:12055638, PMID:32444788, PMID:39521905]. FILIP1 also binds the ATPase domain of non-muscle myosin heavy chain IIb in an Hsc70-dependent manner, regulating myosin IIb subcellular distribution and dendritic spine morphology [PMID:25220605, PMID:28234934]. During myogenic differentiation, FILIP1 transitions from microtubule association (with EB3) to Z-disc localization with FLNc and is recruited to myofibrillar lesion sites upon mechanical stress, functioning as a cytolinker that bridges actin filaments and microtubules during myofibril assembly and repair [PMID:37178194, PMID:29618024].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The question of how Filamin A abundance is controlled in migrating neurons was answered by the discovery that FILIP1 binds Filamin A and induces its degradation, establishing FILIP1 as a regulator of the actin cytoskeleton during neocortical migration.\",\n      \"evidence\": \"Co-immunoprecipitation in COS-7 cells and cortical explant migration assays\",\n      \"pmids\": [\"12055638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Proteolytic pathway mediating FILIP1-induced Filamin A degradation not identified\",\n        \"Whether FILIP1 acts on other filamins unknown\",\n        \"In vivo loss-of-function phenotype not yet established\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The cell-biological consequence of FILIP1-mediated Filamin A control was resolved: FILIP1 determines whether migrating cortical neurons adopt multipolar versus bipolar morphology by titrating Filamin A levels, establishing that FILIP1 is a polarity switch during cortical development.\",\n      \"evidence\": \"siRNA knockdown of FILIP1 in cortical neurons combined with dominant-negative Filamin A and in vivo migration assays\",\n      \"pmids\": [\"15509752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream signals controlling FILIP1 expression in cortical neurons not identified\",\n        \"Whether FILIP1 function is required postnatally unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Beyond filamins, FILIP1 was shown to bind non-muscle myosin heavy chain IIb near its ATPase domain and modulate its actin-binding activity, establishing a second cytoskeletal target and linking FILIP1 to dendritic spine morphology and neural excitation.\",\n      \"evidence\": \"Co-immunoprecipitation, actin-binding interference assay, and FILIP1-knockout mouse electrophysiology\",\n      \"pmids\": [\"25220605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; independent replication of myosin IIb interaction needed\",\n        \"Structural basis of FILIP1–myosin IIb binding unresolved\",\n        \"Whether FILIP1 degrades myosin IIb or only redistributes it not determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The mechanism by which FILIP1 controls myosin IIb distribution was extended by identifying Hsc70 as a required co-factor: Hsc70 binds FILIP1 via a domain distinct from the myosin IIb-binding region, and its ATPase activity is necessary for FILIP1-dependent regulation of spine morphology.\",\n      \"evidence\": \"Pull-down with mass spectrometry identification of Hsc70, ATPase inhibitor experiments in primary neurons\",\n      \"pmids\": [\"28234934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct structural or reconstituted biochemical evidence for a tripartite FILIP1–Hsc70–myosin IIb complex lacking\",\n        \"Whether Hsc70 is also involved in FILIP1-mediated filamin degradation untested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"FILIP1 was placed in a myogenesis regulatory pathway: its expression is controlled by the lncRNA Myolinc, and FILIP1 knockdown impairs myogenic differentiation, revealing a muscle-specific function beyond the neuronal context.\",\n      \"evidence\": \"siRNA knockdown of FILIP1 in C2C12 myoblasts with qRT-PCR and myotube formation assays\",\n      \"pmids\": [\"29618024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the myogenesis role operates through filamin degradation or an independent mechanism not determined\",\n        \"In vivo muscle phenotype of FILIP1 loss not reported\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The question of how FILIP1-mediated filamin degradation is regulated was answered: dual phosphorylation of FLNc Ser2234 (by Akt) and a second site (by PKCα) shields FLNc from FILIP1 binding, establishing a phosphorylation-dependent gating mechanism for FILIP1 activity in muscle.\",\n      \"evidence\": \"BioID proximity proteomics, quantitative phosphoproteomics, kinase inhibitor experiments, and phosphosite mutagenesis\",\n      \"pmids\": [\"32444788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the E3 ligase mediating FILIP1-dependent FLNc proteasomal degradation unknown\",\n        \"Whether the same phospho-switch regulates FILIP1 binding to Filamin A untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"FILIP1's dynamic localization during myogenesis was mapped — it transitions from microtubules (EB3-positive) to Z-discs with FLNc, and both proteins relocate to myofibrillar lesion sites under mechanical stress, establishing FILIP1 as a cytolinker involved in myofibril assembly and damage response.\",\n      \"evidence\": \"Immunofluorescence in differentiating myotubes with electrical pulse stimulation and nocodazole treatment\",\n      \"pmids\": [\"37178194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct microtubule-binding domain in FILIP1 not mapped\",\n        \"Whether FILIP1 promotes repair or degradation at lesion sites not distinguished\",\n        \"Single lab observation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The upstream phosphatase completing the FLNc phospho-switch was identified: PP1 dephosphorylates FLNc Ser2234 under acute mechanical stress, promoting FILIP1 binding and thus coupling mechanical damage sensing to FILIP1-dependent filamin degradation.\",\n      \"evidence\": \"In vitro phosphatase assay, quantitative phosphoproteomics, and PP1 modulator treatments in skeletal myotubes\",\n      \"pmids\": [\"39521905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanosensor upstream of PP1 activation not identified\",\n        \"Whether PP1-FILIP1 axis operates in non-muscle contexts unknown\",\n        \"In vivo validation of PP1-FLNc-FILIP1 axis in muscle injury models lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The E3 ubiquitin ligase that mediates FILIP1-dependent filamin degradation has not been identified, and the structural basis of FILIP1 binding to its multiple cytoskeletal partners (Filamin A, Filamin C, myosin IIb, EB3/microtubules) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No E3 ligase identified for FILIP1-induced proteasomal degradation of filamins\",\n        \"No structural model for any FILIP1 interaction\",\n        \"In vivo muscle phenotype of FILIP1 loss-of-function not reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FLNA\",\n      \"FLNC\",\n      \"MYH10\",\n      \"HSPA8\",\n      \"PPP1CA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}