{"gene":"FILIP1L","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2011,"finding":"FILIP1L (also known as GIP130) was identified as a binding partner of Goodpasture antigen-binding protein-1 (GPBP-1) in differentiating myoblasts. GIP130/FILIP1L binds to myosin and promotes its myofibrillar assembly. GPBP-1 targets GIP130/FILIP1L to direct myofibril formation in the intracellular compartment.","method":"Co-immunoprecipitation, pulldown assays, myoblast overexpression/knockdown with myofibril assembly readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified with functional consequence in myoblast differentiation, single lab with multiple assays","pmids":["21832087"],"is_preprint":false},{"year":2011,"finding":"FILIP1L interacts with Hsf1 (heat shock factor 1), identified by yeast two-hybrid screening, and promotes Hsf1 ubiquitination and degradation through the ubiquitin-proteasome system. FILIP1L, Hsf1, and the ubiquitin-binding domain of HhR23A (a receptor transporting polyubiquitinated proteins to the 19S proteasome) form a complex, indicating FILIP1L acts as an adaptor in the Hsf1 degradation pathway, leading to reduced Hsf1-mediated transcription.","method":"Yeast two-hybrid screening, co-immunoprecipitation, ectopic expression with ubiquitination assay and proteasome inhibitor treatment, reporter assay for Hsf1 transcription","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus Co-IP plus ubiquitination assay plus functional transcription readout, multiple orthogonal methods in one rigorous study","pmids":["21784850"],"is_preprint":false},{"year":2012,"finding":"FILIP1L expression is transcriptionally induced by TOP2-targeting chemotherapeutics (doxorubicin, etoposide, mitoxantrone) but not by TOP2 catalytic inhibitors or UV irradiation. This induction requires the OCT1 transcription factor, which relocalizes to the FILIP1L promoter following doxorubicin treatment. FILIP1L mediates apoptosis triggered by doxorubicin.","method":"shRNA screen, promoter ChIP, transcription factor knockdown/relocalization, cell death assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA screen with functional apoptosis readout and ChIP validation of OCT1 at FILIP1L promoter, single lab","pmids":["22900064"],"is_preprint":false},{"year":2012,"finding":"FILIP1L isoform 2 is silenced in prostate cancer by CpG island hypermethylation 5' of its translational start site. Treatment of prostate cancer cell lines with the demethylating agent 2'-deoxy-5-azacytidine restored isoform 2 expression, establishing epigenetic methylation as a regulatory mechanism for FILIP1L.","method":"Bisulfite sequencing, pyrosequencing, demethylation agent treatment with RT-qPCR, tissue microarray with protein quantification","journal":"The Journal of urology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methylation assays plus pharmacologic demethylation rescue, single lab","pmids":["23174249"],"is_preprint":false},{"year":2020,"finding":"Prmt5-induced H4R3 symmetric di-methylation (H4R3me2s) transcriptionally upregulates FILIP1L. Knockdown or inhibition of Prmt5 impairs FILIP1L transcription and subsequently prevents β-catenin degradation, augmenting cardiomyocyte hypertrophy. ChIP-sequencing identified FILIP1L as a direct target gene of Prmt5-induced H4R3me2s.","method":"ChIP-sequencing, Prmt5 knockdown/overexpression/inactive mutant, cardiomyocyte hypertrophy assay, β-catenin degradation assay","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus genetic loss-of-function with inactive mutant control plus functional β-catenin readout, single lab","pmids":["32739429"],"is_preprint":false},{"year":2021,"finding":"FILIP1L binds to PFDN1 (prefoldin 1) at centrosomes throughout mitosis. FILIP1L is required for proper centrosomal localization of PFDN1 and regulates proteasome-dependent degradation of PFDN1. Loss of FILIP1L leads to increased PFDN1 levels, driving multinucleation and cytokinesis defects. In colon-specific knockout mice, FILIP1L loss induced colonic epithelial hyperplasia and mucin secretion.","method":"Co-immunoprecipitation, time-lapse imaging, 3D cultures, colon-specific knockout mouse model, xenograft growth assay, proteasome inhibitor treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vivo knockout plus time-lapse imaging plus 3D cultures, multiple orthogonal methods, single lab","pmids":["34417201"],"is_preprint":false},{"year":2021,"finding":"In lens epithelial cells, FILIP1L knockdown enhanced EMT and ECM synthesis and promoted cell migration, while FILIP1L overexpression reversed these effects. RNA-seq revealed FILIP1L was significantly decreased in apoptosis-activated cells, placing FILIP1L downstream of TGF-β2-induced apoptosis in regulating EMT/ECM synthesis during posterior capsular opacification.","method":"RNA-seq, siRNA knockdown, overexpression, Western blotting for EMT/ECM markers, wound healing and Transwell migration assays, flow cytometry","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with multiple orthogonal cellular readouts and RNA-seq, single lab","pmids":["34666037"],"is_preprint":false},{"year":2022,"finding":"In lung adenocarcinoma, reduction of FILIP1L and subsequent increase in its binding partner PFDN1 increases mucin secretion, proliferation, inflammation, and fibrosis. RNA-sequencing of syngeneic allograft tumors with reduced FILIP1L showed upregulated Wnt/β-catenin signaling. Cigarette smoking causes FILIP1L downregulation by promoter methylation.","method":"RNA-sequencing of syngeneic allograft tumors, lung-specific knockout mice, xenograft growth assay, methylation analysis","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lung-specific knockout mouse plus RNA-seq plus methylation analysis, single lab","pmids":["36860703"],"is_preprint":false},{"year":2025,"finding":"FILIP1L colocalizes with the mitochondrial outer membrane marker TOM20 by immunofluorescence and high-resolution confocal microscopy, indicating that FILIP1L has mitochondrial localization.","method":"Immunofluorescence staining for endogenous FILIP1L, high-resolution confocal microscopy, colocalization with TOM20","journal":"microPublication biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single colocalization experiment, no functional consequence demonstrated, single lab","pmids":["40206462"],"is_preprint":false},{"year":2025,"finding":"FILIP1L is a novel invadopodia component that colocalizes with invadopodia markers Tks5 and cortactin. Loss of FILIP1L increases ECM degradation but decreases cell migration, resulting in overall decreased 3D spheroid invasion. FILIP1L expression is cell cycle- and EMT-state-dependent, peaking in the invasive phase of each EMT state (G2 in Early E/M cells, G1 in Late E/M cells).","method":"Bulk mRNA sequencing, FILIP1L knockdown, immunofluorescence colocalization with Tks5/cortactin, ECM degradation assay, cell migration assay, 3D spheroid invasion assay, cell cycle sorting","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including RNAseq, KD, colocalization, functional ECM/invasion assays; preprint, single lab","pmids":["41415400"],"is_preprint":true},{"year":2026,"finding":"FILIP1L loss in mouse models results in fewer metastatic colonies, establishing FILIP1L as a regulator of productive invasion that coordinates invadopodia activity with migratory cell states. FILIP1L expression increases with EMT progression.","method":"Mouse in vivo metastasis model with FILIP1L knockdown, bulk mRNA sequencing, cell cycle phase sorting","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse metastasis assay plus mRNA sequencing plus cell cycle analysis; preprint, single lab, overlaps with companion study","pmids":["42040966"],"is_preprint":true}],"current_model":"FILIP1L is a multifunctional scaffold/adaptor protein that (1) promotes ubiquitin-proteasome-dependent degradation of Hsf1 by forming a complex with Hsf1 and HhR23A; (2) localizes to centrosomes during mitosis where it binds PFDN1 and regulates proteasome-dependent PFDN1 degradation, thereby preventing cytokinesis defects and aneuploidy; (3) acts as a novel invadopodia component whose expression is regulated by EMT state and cell cycle phase to coordinate ECM degradation and cell migration; (4) promotes β-catenin degradation downstream of the epigenetic regulator Prmt5; (5) mediates apoptosis downstream of TOP2 poisons via OCT1-driven transcriptional induction; and (6) binds myosin to promote myofibril assembly in differentiating myoblasts, with its expression controlled by CpG island methylation and other epigenetic mechanisms across multiple cancer contexts."},"narrative":{"mechanistic_narrative":"FILIP1L is a scaffold/adaptor protein that couples the ubiquitin-proteasome system to control of transcription factors, cytoskeletal organization, and cell motility [PMID:21784850, PMID:34417201]. It functions as an adaptor in targeted protein degradation: it binds Hsf1 and recruits the ubiquitin-shuttling factor HhR23A to promote Hsf1 ubiquitination, proteasomal degradation, and consequent loss of Hsf1-mediated transcription [PMID:21784850], and at centrosomes it binds PFDN1 throughout mitosis, controlling PFDN1 centrosomal localization and proteasome-dependent turnover so that loss of FILIP1L raises PFDN1 levels and produces multinucleation and cytokinesis defects [PMID:34417201]. FILIP1L expression itself is tightly regulated: it is silenced by CpG island hypermethylation in cancer [PMID:23174249], transcriptionally induced by TOP2-poison chemotherapeutics through OCT1 recruitment to its promoter to mediate apoptosis [PMID:22900064], and upregulated by Prmt5-driven H4R3me2s, where it promotes β-catenin degradation [PMID:32739429]. Through the FILIP1L–PFDN1 axis FILIP1L restrains Wnt/β-catenin signaling, mucin secretion, proliferation and fibrosis in epithelial tissues, with promoter methylation driving its loss in lung adenocarcinoma [PMID:36860703]. FILIP1L is also a component of invadopodia that colocalizes with Tks5 and cortactin and, in a cell-cycle- and EMT-state-dependent manner, coordinates ECM degradation with migratory capacity to enable productive invasion and metastasis [PMID:41415400, PMID:42040966]. In differentiating myoblasts it binds myosin to promote myofibril assembly [PMID:21832087].","teleology":[{"year":2011,"claim":"Established a cytoskeletal role for FILIP1L by showing it binds myosin and drives myofibril assembly, linking it to muscle differentiation.","evidence":"Co-IP and pulldown with GPBP-1, plus myoblast overexpression/knockdown with myofibril assembly readout","pmids":["21832087"],"confidence":"Medium","gaps":["Binding interface to myosin not mapped","No in vivo validation of myofibril phenotype","Relationship to FILIP1L's degradation-adaptor roles unclear"]},{"year":2011,"claim":"Defined FILIP1L as a degradation adaptor by showing it bridges Hsf1 to the proteasome via HhR23A to suppress Hsf1-mediated transcription, the first mechanistic role assigned to the protein.","evidence":"Yeast two-hybrid, Co-IP, ubiquitination assay with proteasome inhibitor, Hsf1 transcription reporter","pmids":["21784850"],"confidence":"High","gaps":["The responsible E3 ligase is not identified","Whether FILIP1L itself confers substrate specificity beyond Hsf1 is unknown"]},{"year":2012,"claim":"Identified the transcriptional control and apoptotic output of FILIP1L by showing TOP2-poison chemotherapeutics induce it through OCT1 to mediate cell death.","evidence":"shRNA screen, promoter ChIP for OCT1, transcription factor knockdown/relocalization, cell death assays","pmids":["22900064"],"confidence":"Medium","gaps":["Downstream effectors of FILIP1L-driven apoptosis not defined","Specificity for TOP2 poisons versus other DNA damage unexplained mechanistically"]},{"year":2012,"claim":"Showed FILIP1L is epigenetically silenced in cancer, establishing promoter CpG methylation as a regulatory mechanism for its expression.","evidence":"Bisulfite sequencing, pyrosequencing, demethylation rescue with RT-qPCR, tissue microarray","pmids":["23174249"],"confidence":"Medium","gaps":["Isoform-specific functional differences not resolved","Causal link between silencing and tumor phenotype not established in this study"]},{"year":2020,"claim":"Connected FILIP1L to Wnt signaling control by showing Prmt5/H4R3me2s upregulates FILIP1L to promote β-catenin degradation and limit cardiomyocyte hypertrophy.","evidence":"ChIP-seq, Prmt5 knockdown/overexpression/inactive mutant, β-catenin degradation and hypertrophy assays","pmids":["32739429"],"confidence":"Medium","gaps":["Mechanism by which FILIP1L promotes β-catenin degradation not defined","Direct vs indirect role in the destruction complex unknown"]},{"year":2021,"claim":"Established FILIP1L's mitotic function by showing it controls centrosomal PFDN1 localization and proteasomal turnover, preventing multinucleation and aneuploidy, with in vivo loss causing colonic hyperplasia.","evidence":"Reciprocal Co-IP, time-lapse imaging, 3D cultures, colon-specific knockout mice, xenografts, proteasome inhibitor","pmids":["34417201"],"confidence":"High","gaps":["E3 ligase mediating PFDN1 degradation unidentified","Structural basis of FILIP1L–PFDN1 binding not resolved"]},{"year":2021,"claim":"Placed FILIP1L downstream of TGF-β2-induced apoptosis as a suppressor of EMT, ECM synthesis, and migration in lens epithelial cells.","evidence":"RNA-seq, siRNA, overexpression, EMT/ECM marker Westerns, migration and flow cytometry assays","pmids":["34666037"],"confidence":"Medium","gaps":["Molecular intermediaries between FILIP1L and EMT markers undefined","Single cell-type context"]},{"year":2022,"claim":"Extended the FILIP1L–PFDN1 axis to lung adenocarcinoma, linking FILIP1L loss to Wnt/β-catenin activation, mucin/fibrosis phenotypes, and smoking-induced promoter methylation.","evidence":"RNA-seq of syngeneic allografts, lung-specific knockout mice, xenografts, methylation analysis","pmids":["36860703"],"confidence":"Medium","gaps":["Direct mechanism linking PFDN1 to Wnt activation not established","Causality of smoking-induced methylation in vivo not formally proven"]},{"year":2025,"claim":"Identified FILIP1L as an invadopodia component coordinating ECM degradation with migration in a cell-cycle- and EMT-state-dependent manner to enable invasion.","evidence":"Bulk RNA-seq, knockdown, colocalization with Tks5/cortactin, ECM degradation, migration and 3D spheroid invasion assays, cell cycle sorting (preprint)","pmids":["41415400"],"confidence":"Medium","gaps":["Mechanism by which FILIP1L balances degradation vs migration unknown","Preprint, single lab"]},{"year":2026,"claim":"Demonstrated in vivo that FILIP1L promotes productive metastatic colonization, integrating invadopodia activity with migratory states.","evidence":"Mouse in vivo metastasis model with knockdown, bulk RNA-seq, cell cycle sorting (preprint)","pmids":["42040966"],"confidence":"Medium","gaps":["Molecular effectors at metastatic sites undefined","Preprint, overlaps with companion study"]},{"year":2025,"claim":"Reported mitochondrial localization of endogenous FILIP1L, raising an unresolved compartment-specific function.","evidence":"Immunofluorescence and confocal colocalization with TOM20","pmids":["40206462"],"confidence":"Low","gaps":["Single colocalization experiment with no functional consequence demonstrated","Not independently confirmed","Relationship to centrosomal/invadopodial roles unknown"]},{"year":null,"claim":"How FILIP1L mechanistically selects its degradation substrates and which E3 ligase machinery it engages remain unresolved across its Hsf1, PFDN1, and β-catenin functions.","evidence":"No timeline study identifies the E3 ligase or a unified substrate-recognition mechanism","pmids":[],"confidence":"Low","gaps":["No E3 ligase identified for any FILIP1L-directed degradation event","No structural model of FILIP1L or its binding interfaces","Mechanism unifying its degradation-adaptor and invadopodia roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["HSF1","RAD23A","PFDN1","GPBP1","TKS5","CTTN","MYH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q4L180","full_name":"Filamin A-interacting protein 1-like","aliases":["130 kDa GPBP-interacting protein","90 kDa GPBP-interacting protein","Protein down-regulated in ovarian cancer 1","DOC-1"],"length_aa":1135,"mass_kda":130.4,"function":"Acts as a regulator of the antiangiogenic activity on endothelial cells. When overexpressed in endothelial cells, leads to inhibition of cell proliferation and migration and an increase in apoptosis. Inhibits melanoma growth When expressed in tumor-associated vasculature","subcellular_location":"Cytoplasm; Membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q4L180/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FILIP1L","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/FILIP1L","total_profiled":1310},"omim":[{"mim_id":"612993","title":"FILAMIN A-INTERACTING PROTEIN 1-LIKE; FILIP1L","url":"https://www.omim.org/entry/612993"},{"mim_id":"603075","title":"MACULAR DEGENERATION, AGE-RELATED, 1; ARMD1","url":"https://www.omim.org/entry/603075"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":191.1}],"url":"https://www.proteinatlas.org/search/FILIP1L"},"hgnc":{"alias_symbol":["DOC-1","GIP130"],"prev_symbol":[]},"alphafold":{"accession":"Q4L180","domains":[{"cath_id":"1.20.5","chopping":"74-110","consensus_level":"medium","plddt":74.0,"start":74,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4L180","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4L180-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4L180-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FILIP1L","jax_strain_url":"https://www.jax.org/strain/search?query=FILIP1L"},"sequence":{"accession":"Q4L180","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4L180.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4L180/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4L180"}},"corpus_meta":[{"pmid":"30651325","id":"PMC_30651325","title":"MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via Targeting Ubr5.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30651325","citation_count":86,"is_preprint":false},{"pmid":"21212092","id":"PMC_21212092","title":"Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high-fat fed mice.","date":"2011","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21212092","citation_count":62,"is_preprint":false},{"pmid":"8532600","id":"PMC_8532600","title":"Characterization of GIP(1-30) and GIP(1-42) as stimulators of proinsulin gene transcription.","date":"1995","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/8532600","citation_count":41,"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":"23174249","id":"PMC_23174249","title":"CpG island hypermethylation frequently silences FILIP1L isoform 2 expression in prostate cancer.","date":"2012","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/23174249","citation_count":26,"is_preprint":false},{"pmid":"32739429","id":"PMC_32739429","title":"Histone H4R3 symmetric di-methylation by Prmt5 protects against cardiac hypertrophy via regulation of Filip1L/β-catenin.","date":"2020","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/32739429","citation_count":25,"is_preprint":false},{"pmid":"26693710","id":"PMC_26693710","title":"Pancreatic glucose-dependent insulinotropic polypeptide (GIP) (1-30) expression is upregulated in diabetes and PEGylated GIP(1-30) can suppress the progression of low-dose-STZ-induced hyperglycaemia in mice.","date":"2015","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/26693710","citation_count":25,"is_preprint":false},{"pmid":"34666037","id":"PMC_34666037","title":"FILIP1L-mediated cell apoptosis, epithelial-mesenchymal transition and extracellular matrix synthesis aggravate posterior capsular opacification.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34666037","citation_count":20,"is_preprint":false},{"pmid":"22900064","id":"PMC_22900064","title":"Sensitivity to TOP2 targeting chemotherapeutics is regulated by Oct1 and FILIP1L.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22900064","citation_count":19,"is_preprint":false},{"pmid":"21513424","id":"PMC_21513424","title":"Efficient inhibition of ovarian cancer by truncation mutant of FILIP1L gene delivered by novel biodegradable cationic heparin-polyethyleneimine nanogels.","date":"2011","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/21513424","citation_count":16,"is_preprint":false},{"pmid":"34417201","id":"PMC_34417201","title":"FILIP1L Loss Is a Driver of Aggressive Mucinous Colorectal Adenocarcinoma and Mediates Cytokinesis Defects through PFDN1.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34417201","citation_count":12,"is_preprint":false},{"pmid":"36860703","id":"PMC_36860703","title":"Smoking-associated Downregulation of FILIP1L Enhances Lung Adenocarcinoma Progression Through Mucin Production, Inflammation, and Fibrosis.","date":"2022","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36860703","citation_count":11,"is_preprint":false},{"pmid":"21832087","id":"PMC_21832087","title":"Goodpasture antigen-binding protein (GPBP) directs myofibril formation: identification of intracellular downstream effector 130-kDa GPBP-interacting protein (GIP130).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832087","citation_count":9,"is_preprint":false},{"pmid":"38552852","id":"PMC_38552852","title":"TDO2 promotes bladder cancer progression via AhR-mediated SPARC/FILIP1L signaling.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38552852","citation_count":7,"is_preprint":false},{"pmid":"34000624","id":"PMC_34000624","title":"Clinically relevant aberrant Filip1l DNA methylation detected in a murine model of cutaneous squamous cell carcinoma.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34000624","citation_count":7,"is_preprint":false},{"pmid":"39464637","id":"PMC_39464637","title":"Tirzepatide, GIP(1-42) and GIP(1-30) display unique signaling profiles at two common GIP receptor variants, E354 and Q354.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39464637","citation_count":4,"is_preprint":false},{"pmid":"40206462","id":"PMC_40206462","title":"Filamin A interacting protein 1-like (FILIP1L) has mitochondrial localization.","date":"2025","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/40206462","citation_count":3,"is_preprint":false},{"pmid":"41415400","id":"PMC_41415400","title":"Cell cycle- and EMT-dependent expression of Filip1L controls invadopodia in breast cancer cells.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41415400","citation_count":0,"is_preprint":false},{"pmid":"42040966","id":"PMC_42040966","title":"EMT and cell cycle control invadopodia and metastasis in breast cancer via Filip1L.","date":"2026","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/42040966","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12164,"output_tokens":2950,"usd":0.040371,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10398,"output_tokens":3725,"usd":0.072557,"stage2_stop_reason":"end_turn"},"total_usd":0.112928,"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\": 2011,\n      \"finding\": \"FILIP1L (also known as GIP130) was identified as a binding partner of Goodpasture antigen-binding protein-1 (GPBP-1) in differentiating myoblasts. GIP130/FILIP1L binds to myosin and promotes its myofibrillar assembly. GPBP-1 targets GIP130/FILIP1L to direct myofibril formation in the intracellular compartment.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, myoblast overexpression/knockdown with myofibril assembly readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified with functional consequence in myoblast differentiation, single lab with multiple assays\",\n      \"pmids\": [\"21832087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FILIP1L interacts with Hsf1 (heat shock factor 1), identified by yeast two-hybrid screening, and promotes Hsf1 ubiquitination and degradation through the ubiquitin-proteasome system. FILIP1L, Hsf1, and the ubiquitin-binding domain of HhR23A (a receptor transporting polyubiquitinated proteins to the 19S proteasome) form a complex, indicating FILIP1L acts as an adaptor in the Hsf1 degradation pathway, leading to reduced Hsf1-mediated transcription.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, ectopic expression with ubiquitination assay and proteasome inhibitor treatment, reporter assay for Hsf1 transcription\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus Co-IP plus ubiquitination assay plus functional transcription readout, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"21784850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FILIP1L expression is transcriptionally induced by TOP2-targeting chemotherapeutics (doxorubicin, etoposide, mitoxantrone) but not by TOP2 catalytic inhibitors or UV irradiation. This induction requires the OCT1 transcription factor, which relocalizes to the FILIP1L promoter following doxorubicin treatment. FILIP1L mediates apoptosis triggered by doxorubicin.\",\n      \"method\": \"shRNA screen, promoter ChIP, transcription factor knockdown/relocalization, cell death assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA screen with functional apoptosis readout and ChIP validation of OCT1 at FILIP1L promoter, single lab\",\n      \"pmids\": [\"22900064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FILIP1L isoform 2 is silenced in prostate cancer by CpG island hypermethylation 5' of its translational start site. Treatment of prostate cancer cell lines with the demethylating agent 2'-deoxy-5-azacytidine restored isoform 2 expression, establishing epigenetic methylation as a regulatory mechanism for FILIP1L.\",\n      \"method\": \"Bisulfite sequencing, pyrosequencing, demethylation agent treatment with RT-qPCR, tissue microarray with protein quantification\",\n      \"journal\": \"The Journal of urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methylation assays plus pharmacologic demethylation rescue, single lab\",\n      \"pmids\": [\"23174249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Prmt5-induced H4R3 symmetric di-methylation (H4R3me2s) transcriptionally upregulates FILIP1L. Knockdown or inhibition of Prmt5 impairs FILIP1L transcription and subsequently prevents β-catenin degradation, augmenting cardiomyocyte hypertrophy. ChIP-sequencing identified FILIP1L as a direct target gene of Prmt5-induced H4R3me2s.\",\n      \"method\": \"ChIP-sequencing, Prmt5 knockdown/overexpression/inactive mutant, cardiomyocyte hypertrophy assay, β-catenin degradation assay\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus genetic loss-of-function with inactive mutant control plus functional β-catenin readout, single lab\",\n      \"pmids\": [\"32739429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FILIP1L binds to PFDN1 (prefoldin 1) at centrosomes throughout mitosis. FILIP1L is required for proper centrosomal localization of PFDN1 and regulates proteasome-dependent degradation of PFDN1. Loss of FILIP1L leads to increased PFDN1 levels, driving multinucleation and cytokinesis defects. In colon-specific knockout mice, FILIP1L loss induced colonic epithelial hyperplasia and mucin secretion.\",\n      \"method\": \"Co-immunoprecipitation, time-lapse imaging, 3D cultures, colon-specific knockout mouse model, xenograft growth assay, proteasome inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vivo knockout plus time-lapse imaging plus 3D cultures, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34417201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In lens epithelial cells, FILIP1L knockdown enhanced EMT and ECM synthesis and promoted cell migration, while FILIP1L overexpression reversed these effects. RNA-seq revealed FILIP1L was significantly decreased in apoptosis-activated cells, placing FILIP1L downstream of TGF-β2-induced apoptosis in regulating EMT/ECM synthesis during posterior capsular opacification.\",\n      \"method\": \"RNA-seq, siRNA knockdown, overexpression, Western blotting for EMT/ECM markers, wound healing and Transwell migration assays, flow cytometry\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with multiple orthogonal cellular readouts and RNA-seq, single lab\",\n      \"pmids\": [\"34666037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In lung adenocarcinoma, reduction of FILIP1L and subsequent increase in its binding partner PFDN1 increases mucin secretion, proliferation, inflammation, and fibrosis. RNA-sequencing of syngeneic allograft tumors with reduced FILIP1L showed upregulated Wnt/β-catenin signaling. Cigarette smoking causes FILIP1L downregulation by promoter methylation.\",\n      \"method\": \"RNA-sequencing of syngeneic allograft tumors, lung-specific knockout mice, xenograft growth assay, methylation analysis\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lung-specific knockout mouse plus RNA-seq plus methylation analysis, single lab\",\n      \"pmids\": [\"36860703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FILIP1L colocalizes with the mitochondrial outer membrane marker TOM20 by immunofluorescence and high-resolution confocal microscopy, indicating that FILIP1L has mitochondrial localization.\",\n      \"method\": \"Immunofluorescence staining for endogenous FILIP1L, high-resolution confocal microscopy, colocalization with TOM20\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single colocalization experiment, no functional consequence demonstrated, single lab\",\n      \"pmids\": [\"40206462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FILIP1L is a novel invadopodia component that colocalizes with invadopodia markers Tks5 and cortactin. Loss of FILIP1L increases ECM degradation but decreases cell migration, resulting in overall decreased 3D spheroid invasion. FILIP1L expression is cell cycle- and EMT-state-dependent, peaking in the invasive phase of each EMT state (G2 in Early E/M cells, G1 in Late E/M cells).\",\n      \"method\": \"Bulk mRNA sequencing, FILIP1L knockdown, immunofluorescence colocalization with Tks5/cortactin, ECM degradation assay, cell migration assay, 3D spheroid invasion assay, cell cycle sorting\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including RNAseq, KD, colocalization, functional ECM/invasion assays; preprint, single lab\",\n      \"pmids\": [\"41415400\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FILIP1L loss in mouse models results in fewer metastatic colonies, establishing FILIP1L as a regulator of productive invasion that coordinates invadopodia activity with migratory cell states. FILIP1L expression increases with EMT progression.\",\n      \"method\": \"Mouse in vivo metastasis model with FILIP1L knockdown, bulk mRNA sequencing, cell cycle phase sorting\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse metastasis assay plus mRNA sequencing plus cell cycle analysis; preprint, single lab, overlaps with companion study\",\n      \"pmids\": [\"42040966\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"FILIP1L is a multifunctional scaffold/adaptor protein that (1) promotes ubiquitin-proteasome-dependent degradation of Hsf1 by forming a complex with Hsf1 and HhR23A; (2) localizes to centrosomes during mitosis where it binds PFDN1 and regulates proteasome-dependent PFDN1 degradation, thereby preventing cytokinesis defects and aneuploidy; (3) acts as a novel invadopodia component whose expression is regulated by EMT state and cell cycle phase to coordinate ECM degradation and cell migration; (4) promotes β-catenin degradation downstream of the epigenetic regulator Prmt5; (5) mediates apoptosis downstream of TOP2 poisons via OCT1-driven transcriptional induction; and (6) binds myosin to promote myofibril assembly in differentiating myoblasts, with its expression controlled by CpG island methylation and other epigenetic mechanisms across multiple cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FILIP1L is a scaffold/adaptor protein that couples the ubiquitin-proteasome system to control of transcription factors, cytoskeletal organization, and cell motility [#1, #5]. It functions as an adaptor in targeted protein degradation: it binds Hsf1 and recruits the ubiquitin-shuttling factor HhR23A to promote Hsf1 ubiquitination, proteasomal degradation, and consequent loss of Hsf1-mediated transcription [#1], and at centrosomes it binds PFDN1 throughout mitosis, controlling PFDN1 centrosomal localization and proteasome-dependent turnover so that loss of FILIP1L raises PFDN1 levels and produces multinucleation and cytokinesis defects [#5]. FILIP1L expression itself is tightly regulated: it is silenced by CpG island hypermethylation in cancer [#3], transcriptionally induced by TOP2-poison chemotherapeutics through OCT1 recruitment to its promoter to mediate apoptosis [#2], and upregulated by Prmt5-driven H4R3me2s, where it promotes \\u03b2-catenin degradation [#4]. Through the FILIP1L\\u2013PFDN1 axis FILIP1L restrains Wnt/\\u03b2-catenin signaling, mucin secretion, proliferation and fibrosis in epithelial tissues, with promoter methylation driving its loss in lung adenocarcinoma [#7]. FILIP1L is also a component of invadopodia that colocalizes with Tks5 and cortactin and, in a cell-cycle- and EMT-state-dependent manner, coordinates ECM degradation with migratory capacity to enable productive invasion and metastasis [#9, #10]. In differentiating myoblasts it binds myosin to promote myofibril assembly [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established a cytoskeletal role for FILIP1L by showing it binds myosin and drives myofibril assembly, linking it to muscle differentiation.\",\n      \"evidence\": \"Co-IP and pulldown with GPBP-1, plus myoblast overexpression/knockdown with myofibril assembly readout\",\n      \"pmids\": [\"21832087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface to myosin not mapped\", \"No in vivo validation of myofibril phenotype\", \"Relationship to FILIP1L's degradation-adaptor roles unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined FILIP1L as a degradation adaptor by showing it bridges Hsf1 to the proteasome via HhR23A to suppress Hsf1-mediated transcription, the first mechanistic role assigned to the protein.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ubiquitination assay with proteasome inhibitor, Hsf1 transcription reporter\",\n      \"pmids\": [\"21784850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The responsible E3 ligase is not identified\", \"Whether FILIP1L itself confers substrate specificity beyond Hsf1 is unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the transcriptional control and apoptotic output of FILIP1L by showing TOP2-poison chemotherapeutics induce it through OCT1 to mediate cell death.\",\n      \"evidence\": \"shRNA screen, promoter ChIP for OCT1, transcription factor knockdown/relocalization, cell death assays\",\n      \"pmids\": [\"22900064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of FILIP1L-driven apoptosis not defined\", \"Specificity for TOP2 poisons versus other DNA damage unexplained mechanistically\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed FILIP1L is epigenetically silenced in cancer, establishing promoter CpG methylation as a regulatory mechanism for its expression.\",\n      \"evidence\": \"Bisulfite sequencing, pyrosequencing, demethylation rescue with RT-qPCR, tissue microarray\",\n      \"pmids\": [\"23174249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific functional differences not resolved\", \"Causal link between silencing and tumor phenotype not established in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected FILIP1L to Wnt signaling control by showing Prmt5/H4R3me2s upregulates FILIP1L to promote \\u03b2-catenin degradation and limit cardiomyocyte hypertrophy.\",\n      \"evidence\": \"ChIP-seq, Prmt5 knockdown/overexpression/inactive mutant, \\u03b2-catenin degradation and hypertrophy assays\",\n      \"pmids\": [\"32739429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FILIP1L promotes \\u03b2-catenin degradation not defined\", \"Direct vs indirect role in the destruction complex unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established FILIP1L's mitotic function by showing it controls centrosomal PFDN1 localization and proteasomal turnover, preventing multinucleation and aneuploidy, with in vivo loss causing colonic hyperplasia.\",\n      \"evidence\": \"Reciprocal Co-IP, time-lapse imaging, 3D cultures, colon-specific knockout mice, xenografts, proteasome inhibitor\",\n      \"pmids\": [\"34417201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating PFDN1 degradation unidentified\", \"Structural basis of FILIP1L\\u2013PFDN1 binding not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed FILIP1L downstream of TGF-\\u03b22-induced apoptosis as a suppressor of EMT, ECM synthesis, and migration in lens epithelial cells.\",\n      \"evidence\": \"RNA-seq, siRNA, overexpression, EMT/ECM marker Westerns, migration and flow cytometry assays\",\n      \"pmids\": [\"34666037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular intermediaries between FILIP1L and EMT markers undefined\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the FILIP1L\\u2013PFDN1 axis to lung adenocarcinoma, linking FILIP1L loss to Wnt/\\u03b2-catenin activation, mucin/fibrosis phenotypes, and smoking-induced promoter methylation.\",\n      \"evidence\": \"RNA-seq of syngeneic allografts, lung-specific knockout mice, xenografts, methylation analysis\",\n      \"pmids\": [\"36860703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking PFDN1 to Wnt activation not established\", \"Causality of smoking-induced methylation in vivo not formally proven\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FILIP1L as an invadopodia component coordinating ECM degradation with migration in a cell-cycle- and EMT-state-dependent manner to enable invasion.\",\n      \"evidence\": \"Bulk RNA-seq, knockdown, colocalization with Tks5/cortactin, ECM degradation, migration and 3D spheroid invasion assays, cell cycle sorting (preprint)\",\n      \"pmids\": [\"41415400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FILIP1L balances degradation vs migration unknown\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated in vivo that FILIP1L promotes productive metastatic colonization, integrating invadopodia activity with migratory states.\",\n      \"evidence\": \"Mouse in vivo metastasis model with knockdown, bulk RNA-seq, cell cycle sorting (preprint)\",\n      \"pmids\": [\"42040966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors at metastatic sites undefined\", \"Preprint, overlaps with companion study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported mitochondrial localization of endogenous FILIP1L, raising an unresolved compartment-specific function.\",\n      \"evidence\": \"Immunofluorescence and confocal colocalization with TOM20\",\n      \"pmids\": [\"40206462\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single colocalization experiment with no functional consequence demonstrated\", \"Not independently confirmed\", \"Relationship to centrosomal/invadopodial roles unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FILIP1L mechanistically selects its degradation substrates and which E3 ligase machinery it engages remain unresolved across its Hsf1, PFDN1, and \\u03b2-catenin functions.\",\n      \"evidence\": \"No timeline study identifies the E3 ligase or a unified substrate-recognition mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No E3 ligase identified for any FILIP1L-directed degradation event\", \"No structural model of FILIP1L or its binding interfaces\", \"Mechanism unifying its degradation-adaptor and invadopodia roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSF1\", \"RAD23A\", \"PFDN1\", \"GPBP1\", \"TKS5\", \"CTTN\", \"MYH\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}