{"gene":"FBLN5","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1999,"finding":"FBLN5 (DANCE) is a secreted 66-kDa extracellular matrix protein containing six calcium-binding EGF-like domains and an RGD motif that promotes endothelial cell adhesion through interaction with integrin receptors via its RGD motif.","method":"Recombinant protein overexpression, cell adhesion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct cell adhesion assay with recombinant protein, RGD-integrin interaction established, replicated in subsequent papers","pmids":["10428823"],"is_preprint":false},{"year":1999,"finding":"FBLN5 (EVEC) mRNA is predominantly expressed in VSMCs of developing arteries and is dramatically downregulated in adult arteries but re-induced following vascular injury, suggesting a role in vascular growth and maturation.","method":"In situ hybridization, subtraction hybridization","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 3 — in situ hybridization localization with functional context, single lab","pmids":["10347091"],"is_preprint":false},{"year":2002,"finding":"TGF-β stimulates fibulin-5 (FBLN5) transcript and protein synthesis in 3T3-L1 fibroblasts through a Smad3-independent pathway; FBLN5 overexpression enhances basal and TGF-β-stimulated activation of ERK1/ERK2 and p38 MAPK.","method":"Overexpression studies, dominant-negative constructs, kinase activity assays, DNA synthesis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including dominant-negative rescue and kinase assays in a single study","pmids":["12021267"],"is_preprint":false},{"year":2002,"finding":"A homozygous missense mutation (S227P) in the fourth calcium-binding EGF-like domain of FBLN5 causes autosomal recessive cutis laxa in humans, implicating FBLN5 in normal elastogenesis.","method":"Human genetic mapping, Sanger sequencing, structural prediction","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — disease-causing mutation identified and linked to elastogenesis function, but mechanism inferred from structural prediction","pmids":["12189163"],"is_preprint":false},{"year":2002,"finding":"FBLN5 is an integrin-binding extracellular matrix protein that acts as a calcium-dependent elastin-binding protein, scaffolding cells to elastic fibers and preventing elastinopathy in skin, lung, and vasculature.","method":"Knockout mouse model, biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — loss-of-function (knockout) with defined phenotype replicated across multiple labs, plus biochemical binding data","pmids":["12021267"],"is_preprint":false},{"year":2003,"finding":"A heterozygous tandem duplication in FBLN5 (encoding four extra calcium-binding EGF-like motifs) results in synthesis and secretion of a mutant FBLN5 protein causing cutis laxa, demonstrating that proper EGF-like domain number is required for normal function.","method":"mRNA analysis, protein expression (synthesis/secretion assay), gene duplication mapping","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct demonstration of mutant protein synthesis and secretion, single lab","pmids":["12618961"],"is_preprint":false},{"year":2003,"finding":"FBLN5 is coordinately expressed and regulated with elastin in lung fibroblasts; it localizes to the fibroblast cell layer and is degraded by elastase, and its expression is abolished by IL-1β, indicating a role in lung injury repair.","method":"Western blot, immunohistochemistry, in vitro elastase treatment, cytokine treatment of fibroblasts","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct protein localization and degradation assay with functional cytokine regulation, single lab","pmids":["12909585"],"is_preprint":false},{"year":2007,"finding":"Fibulin-5 acts as an elastogenic organizer by: (1) depositing on microfibrils to promote coacervation and alignment of tropoelastin, and (2) tethering lysyl oxidase-like 1, 2, and 4 enzymes to facilitate tropoelastin crosslinking. Recombinant fibulin-5 induces elastic fiber assembly even in serum-free conditions. A truncated form of fibulin-5 that accumulates with age cannot promote elastogenesis.","method":"Elastogenesis assays with recombinant protein, knockdown of FBLN5, co-localization and biochemical interaction assays with LOXL enzymes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution of elastogenesis with recombinant protein, multiple functional readouts, mechanistic dissection of enzyme tethering","pmids":["17371835"],"is_preprint":false},{"year":2007,"finding":"Latent TGF-β-binding protein 2 (LTBP-2) physically binds FBLN5 (DANCE) and regulates elastic fiber assembly by promoting targeting of FBLN5 onto fibrillin-1 microfibrils; knockdown of LTBP-2 induces fibrillin-1-independent fibrillar deposition of FBLN5 and elastin.","method":"Co-immunoprecipitation/binding protein identification, elastogenesis assay in human skin fibroblasts, siRNA knockdown, recombinant LTBP-2 addition","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — binding partner identified with functional consequence validated by knockdown and recombinant protein rescue in elastogenesis assay","pmids":["17581631"],"is_preprint":false},{"year":2021,"finding":"LOXL1 interacts with FBLN5, which in turn engages αvβ3 integrin in an RGD domain-dependent manner to activate the FAK-MAPK signaling pathway inside vascular endothelial cells, promoting angiogenesis.","method":"Co-immunoprecipitation, overexpression/knockdown, RGD domain mutation, in vitro and in vivo proliferation/metastasis assays","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and domain-mutation demonstrating RGD-dependent integrin engagement with downstream FAK-MAPK activation","pmids":["33614230"],"is_preprint":false},{"year":2012,"finding":"miR-200c directly targets the 3' UTR of FBLN5 mRNA and represses its expression, as validated by luciferase reporter assay.","method":"Luciferase reporter assay with 3' UTR, gain-of-function miR-200c transfection","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3' UTR luciferase validation of miR-200c targeting FBLN5, single lab","pmids":["22685266"],"is_preprint":false},{"year":2021,"finding":"miR-370-3p directly targets FBLN5, inhibiting its expression and activating the NF-κB signaling pathway to promote breast cancer cell proliferation, migration, and stemness.","method":"Luciferase reporter assay, overexpression/knockdown of miR-370-3p, western blot, in vitro and in vivo functional assays","journal":"Stem cells international","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3' UTR luciferase reporter validation, functional rescue experiments, single lab","pmids":["34475958"],"is_preprint":false},{"year":2020,"finding":"miR-27a-3p negatively regulates FBLN5 by directly binding to its 3' UTR, as shown by dual-luciferase reporter assay; FBLN5 overexpression inhibits migration, invasion, and proliferation of ovarian cancer cells.","method":"Dual-luciferase reporter assay, overexpression functional assays (migration, invasion, proliferation)","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3' UTR validation plus functional overexpression phenotype, single lab","pmids":["32901854"],"is_preprint":false},{"year":2023,"finding":"NDUFS1 reduction leads to activation of mitochondrial ROS-HIF1α signaling, which transcriptionally upregulates FBLN5 expression in gastric cancer cells, identifying FBLN5 as a transcriptional target of HIF1α downstream of mROS.","method":"Western blot, confocal microscopy, knockdown/overexpression, in vitro and in vivo functional assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement of FBLN5 as HIF1α transcriptional target via mROS signaling, single lab","pmids":["37644092"],"is_preprint":false},{"year":2017,"finding":"A heterozygous mutation (c.1117C>T) in FBLN5 causes adult-onset demyelinating neuropathy (autosomal dominant Charcot-Marie-Tooth disease type 1), demonstrating FBLN5's role in peripheral nerve maintenance.","method":"Genetic sequencing, nerve biopsy (histopathology), nerve conduction velocity studies","journal":"Clinical neuropathology","confidence":"Medium","confidence_rationale":"Tier 2 — mutation identified with neuropathological validation by biopsy, but mechanistic link to FBLN5 function not fully resolved","pmids":["28332470"],"is_preprint":false}],"current_model":"FBLN5 (fibulin-5/DANCE/EVEC) is a secreted extracellular matrix glycoprotein that functions as an elastogenic organizer by depositing on fibrillin-1 microfibrils, promoting tropoelastin coacervation and alignment, and tethering lysyl oxidase-like enzymes (LOXL1/2/4) to crosslink tropoelastin into mature elastic fibers; it also mediates cell adhesion and signaling through RGD-dependent binding to integrins (αvβ3, αvβ5, α9β1) to activate FAK-MAPK pathways, is induced by TGF-β through a Smad3-independent mechanism to modulate ERK and p38 MAPK activity, and is regulated post-transcriptionally by multiple miRNAs (miR-200c, miR-27a-3p, miR-370-3p) targeting its 3' UTR."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that FBLN5 is a secreted ECM protein with an RGD-integrin cell-adhesion function resolved the question of how this novel fibulin family member mediates cell-matrix interactions.","evidence":"Recombinant FBLN5 protein expression and cell adhesion assays demonstrating RGD-dependent integrin binding","pmids":["10428823"],"confidence":"High","gaps":["Specific integrin receptor subtypes not fully defined","Downstream intracellular signaling from integrin engagement not characterized","In vivo adhesion function not tested"]},{"year":1999,"claim":"Demonstrating that FBLN5 is highly expressed in developing arteries and re-induced after vascular injury established it as a dynamically regulated vascular ECM component rather than a constitutive structural protein.","evidence":"In situ hybridization and subtraction hybridization in mouse vascular tissues","pmids":["10347091"],"confidence":"Medium","gaps":["Functional consequence of re-induction after injury not tested","Transcriptional regulators of FBLN5 in vascular development unknown"]},{"year":2002,"claim":"Linking TGF-β to FBLN5 induction via a Smad3-independent route and showing that FBLN5 amplifies ERK and p38 MAPK signaling revealed FBLN5 as both a target and modulator of growth factor pathways.","evidence":"Overexpression, dominant-negative constructs, and kinase assays in 3T3-L1 fibroblasts","pmids":["12021267"],"confidence":"High","gaps":["Identity of the Smad3-independent TGF-β signaling intermediate unknown","Whether MAPK amplification requires integrin engagement not tested"]},{"year":2002,"claim":"Identification of a homozygous S227P mutation causing autosomal recessive cutis laxa directly linked FBLN5 to human elastogenesis and elastic tissue disease.","evidence":"Genetic mapping and Sanger sequencing in affected families","pmids":["12189163"],"confidence":"Medium","gaps":["Molecular mechanism by which S227P disrupts FBLN5 function not determined biochemically","No rescue experiment performed"]},{"year":2003,"claim":"Demonstration that a tandem duplication adding extra EGF-like domains also causes cutis laxa established that the precise domain architecture of FBLN5 is essential for elastogenic function.","evidence":"mRNA and protein analysis of mutant FBLN5 from an affected individual","pmids":["12618961"],"confidence":"Medium","gaps":["Whether the mutant protein acts in a dominant-negative fashion or is simply nonfunctional was not resolved","Elastogenesis assay with the duplicated protein not performed"]},{"year":2007,"claim":"Reconstitution experiments established FBLN5 as the elastogenic organizer by showing it deposits on fibrillin-1 microfibrils, promotes tropoelastin coacervation, and tethers LOXL1/2/4 for crosslinking—resolving how elastic fiber assembly is coordinated.","evidence":"Recombinant FBLN5 elastogenesis assays, knockdown, co-localization and binding assays with LOXL enzymes in cultured cells","pmids":["17371835"],"confidence":"High","gaps":["Structural basis of FBLN5–LOXL interaction not determined","Whether age-related truncated FBLN5 actively inhibits elastogenesis or is merely inactive not fully resolved"]},{"year":2007,"claim":"Identifying LTBP-2 as a physical binding partner that targets FBLN5 onto fibrillin-1 microfibrils explained how FBLN5 is spatially directed during elastic fiber assembly.","evidence":"Co-immunoprecipitation, siRNA knockdown of LTBP-2, and recombinant rescue in human skin fibroblasts","pmids":["17581631"],"confidence":"High","gaps":["Binding interface between LTBP-2 and FBLN5 not mapped","In vivo validation of LTBP-2 requirement for FBLN5 microfibrillar deposition not shown"]},{"year":2017,"claim":"A heterozygous FBLN5 mutation causing autosomal dominant demyelinating neuropathy extended FBLN5's disease spectrum beyond elastic tissue disorders to peripheral nerve maintenance.","evidence":"Genetic sequencing with nerve biopsy and conduction studies in an affected family","pmids":["28332470"],"confidence":"Medium","gaps":["Mechanism by which FBLN5 mutation leads to demyelination is unknown","Not independently replicated in additional families","No functional assay of mutant protein in nerve tissue"]},{"year":2021,"claim":"Demonstrating that LOXL1–FBLN5–αvβ3 integrin forms a signaling axis activating FAK-MAPK in endothelial cells linked the elastogenic scaffold function of FBLN5 to intracellular pro-angiogenic signaling.","evidence":"Co-immunoprecipitation, RGD domain mutation, knockdown/overexpression in vascular endothelial cells with in vitro and in vivo functional assays","pmids":["33614230"],"confidence":"Medium","gaps":["Whether FAK-MAPK activation is independent of elastic fiber context not resolved","Stoichiometry and direct vs. indirect nature of the ternary complex unclear"]},{"year":2023,"claim":"Placement of FBLN5 as a transcriptional target of HIF1α downstream of mitochondrial ROS revealed an oxygen-sensing transcriptional input for FBLN5 regulation in cancer.","evidence":"Knockdown/overexpression of NDUFS1, Western blot, confocal microscopy in gastric cancer cells","pmids":["37644092"],"confidence":"Medium","gaps":["Direct HIF1α binding to FBLN5 promoter not shown by ChIP","Relevance of this axis to normal elastic tissue homeostasis unknown"]},{"year":null,"claim":"The structural basis of FBLN5 interactions with tropoelastin, LOXL enzymes, and LTBP-2 remains unresolved, and the mechanism by which FBLN5 mutations cause demyelinating neuropathy is unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of FBLN5 or its complexes","Mechanism of FBLN5 in peripheral nerve maintenance entirely uncharacterized","Whether age-related truncation of FBLN5 is a regulated process or a degradation artifact is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,9]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,4,7,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6,7]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9]}],"complexes":[],"partners":["LOXL1","LOXL2","LOXL4","LTBP2","FBN1","ITGAV","ITGB3"],"other_free_text":[]},"mechanistic_narrative":"FBLN5 is a secreted extracellular matrix glycoprotein that serves as the central organizer of elastic fiber assembly and mediates integrin-dependent cell signaling in vascular, dermal, and pulmonary tissues. It deposits on fibrillin-1 microfibrils—guided by LTBP-2—to promote tropoelastin coacervation and tethers lysyl oxidase-like enzymes (LOXL1/2/4) for tropoelastin crosslinking into mature elastic fibers [PMID:17371835, PMID:17581631]. Through its RGD motif, FBLN5 binds integrins (αvβ3, αvβ5, α9β1) to activate FAK-MAPK signaling, and its expression is induced by TGF-β via a Smad3-independent pathway and transcriptionally regulated by HIF1α downstream of mitochondrial ROS [PMID:10428823, PMID:12021267, PMID:33614230, PMID:37644092]. Loss-of-function mutations in FBLN5 cause autosomal recessive cutis laxa, and a heterozygous FBLN5 mutation has been identified in autosomal dominant demyelinating neuropathy [PMID:12189163, PMID:28332470]."},"prefetch_data":{"uniprot":{"accession":"Q9UBX5","full_name":"Fibulin-5","aliases":["Developmental arteries and neural crest EGF-like protein","Dance","Urine p50 protein","UP50"],"length_aa":448,"mass_kda":50.2,"function":"Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN (PubMed:18185537). Stabilizes and organizes elastic fibers in the skin, lung and vasculature (By similarity). Promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. Vascular ligand for integrin receptors which may play a role in vascular development and remodeling (PubMed:10428823). May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108)","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9UBX5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBLN5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBLN5","total_profiled":1310},"omim":[{"mim_id":"620025","title":"DIAPHRAGMATIC HERNIA 4, WITH CARDIOVASCULAR DEFECTS; DIH4","url":"https://www.omim.org/entry/620025"},{"mim_id":"619764","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1H; CMT1H","url":"https://www.omim.org/entry/619764"},{"mim_id":"614437","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IB; ARCL1B","url":"https://www.omim.org/entry/614437"},{"mim_id":"614434","title":"CUTIS LAXA, AUTOSOMAL DOMINANT 2; ADCL2","url":"https://www.omim.org/entry/614434"},{"mim_id":"613177","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IC; ARCL1C","url":"https://www.omim.org/entry/613177"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":668.4}],"url":"https://www.proteinatlas.org/search/FBLN5"},"hgnc":{"alias_symbol":["EVEC","UP50","DANCE","ARMD3"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBX5","domains":[{"cath_id":"-","chopping":"30-69","consensus_level":"high","plddt":76.7325,"start":30,"end":69},{"cath_id":"2.10.25","chopping":"123-166","consensus_level":"medium","plddt":86.8525,"start":123,"end":166},{"cath_id":"2.10.25.10","chopping":"170-206","consensus_level":"medium","plddt":91.2211,"start":170,"end":206},{"cath_id":"2.10.25.10","chopping":"209-246","consensus_level":"medium","plddt":92.5758,"start":209,"end":246},{"cath_id":"2.10.25.10","chopping":"249-287","consensus_level":"medium","plddt":94.2069,"start":249,"end":287},{"cath_id":"2.60.40.60","chopping":"324-442","consensus_level":"high","plddt":93.9911,"start":324,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBX5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBX5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBX5-F1-predicted_aligned_error_v6.png","plddt_mean":83.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBLN5","jax_strain_url":"https://www.jax.org/strain/search?query=FBLN5"},"sequence":{"accession":"Q9UBX5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBX5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBX5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBX5"}},"corpus_meta":[{"pmid":"29149100","id":"PMC_29149100","title":"BCL-2 family proteins: changing partners in the dance towards death.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29149100","citation_count":1175,"is_preprint":false},{"pmid":"18711432","id":"PMC_18711432","title":"How chemokines invite leukocytes to dance.","date":"2008","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18711432","citation_count":242,"is_preprint":false},{"pmid":"12189163","id":"PMC_12189163","title":"Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12189163","citation_count":221,"is_preprint":false},{"pmid":"26882551","id":"PMC_26882551","title":"The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/26882551","citation_count":196,"is_preprint":false},{"pmid":"10428823","id":"PMC_10428823","title":"DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10428823","citation_count":161,"is_preprint":false},{"pmid":"10717670","id":"PMC_10717670","title":"Actin and the agile spine: how and why do dendritic spines dance?","date":"2000","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/10717670","citation_count":146,"is_preprint":false},{"pmid":"15165605","id":"PMC_15165605","title":"Multistep entry of rotavirus into cells: a Versaillesque dance.","date":"2004","source":"Trends in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15165605","citation_count":145,"is_preprint":false},{"pmid":"22305351","id":"PMC_22305351","title":"Neurocognitive control in dance perception and performance.","date":"2012","source":"Acta psychologica","url":"https://pubmed.ncbi.nlm.nih.gov/22305351","citation_count":141,"is_preprint":false},{"pmid":"12021267","id":"PMC_12021267","title":"Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. 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FBLN5 overexpression enhances basal and TGF-β-stimulated activation of ERK1/ERK2 and p38 MAPK.\",\n      \"method\": \"Overexpression studies, dominant-negative constructs, kinase activity assays, DNA synthesis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including dominant-negative rescue and kinase assays in a single study\",\n      \"pmids\": [\"12021267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A homozygous missense mutation (S227P) in the fourth calcium-binding EGF-like domain of FBLN5 causes autosomal recessive cutis laxa in humans, implicating FBLN5 in normal elastogenesis.\",\n      \"method\": \"Human genetic mapping, Sanger sequencing, structural prediction\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — disease-causing mutation identified and linked to elastogenesis function, but mechanism inferred from structural prediction\",\n      \"pmids\": [\"12189163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FBLN5 is an integrin-binding extracellular matrix protein that acts as a calcium-dependent elastin-binding protein, scaffolding cells to elastic fibers and preventing elastinopathy in skin, lung, and vasculature.\",\n      \"method\": \"Knockout mouse model, biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — loss-of-function (knockout) with defined phenotype replicated across multiple labs, plus biochemical binding data\",\n      \"pmids\": [\"12021267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A heterozygous tandem duplication in FBLN5 (encoding four extra calcium-binding EGF-like motifs) results in synthesis and secretion of a mutant FBLN5 protein causing cutis laxa, demonstrating that proper EGF-like domain number is required for normal function.\",\n      \"method\": \"mRNA analysis, protein expression (synthesis/secretion assay), gene duplication mapping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct demonstration of mutant protein synthesis and secretion, single lab\",\n      \"pmids\": [\"12618961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FBLN5 is coordinately expressed and regulated with elastin in lung fibroblasts; it localizes to the fibroblast cell layer and is degraded by elastase, and its expression is abolished by IL-1β, indicating a role in lung injury repair.\",\n      \"method\": \"Western blot, immunohistochemistry, in vitro elastase treatment, cytokine treatment of fibroblasts\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct protein localization and degradation assay with functional cytokine regulation, single lab\",\n      \"pmids\": [\"12909585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fibulin-5 acts as an elastogenic organizer by: (1) depositing on microfibrils to promote coacervation and alignment of tropoelastin, and (2) tethering lysyl oxidase-like 1, 2, and 4 enzymes to facilitate tropoelastin crosslinking. Recombinant fibulin-5 induces elastic fiber assembly even in serum-free conditions. A truncated form of fibulin-5 that accumulates with age cannot promote elastogenesis.\",\n      \"method\": \"Elastogenesis assays with recombinant protein, knockdown of FBLN5, co-localization and biochemical interaction assays with LOXL enzymes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution of elastogenesis with recombinant protein, multiple functional readouts, mechanistic dissection of enzyme tethering\",\n      \"pmids\": [\"17371835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Latent TGF-β-binding protein 2 (LTBP-2) physically binds FBLN5 (DANCE) and regulates elastic fiber assembly by promoting targeting of FBLN5 onto fibrillin-1 microfibrils; knockdown of LTBP-2 induces fibrillin-1-independent fibrillar deposition of FBLN5 and elastin.\",\n      \"method\": \"Co-immunoprecipitation/binding protein identification, elastogenesis assay in human skin fibroblasts, siRNA knockdown, recombinant LTBP-2 addition\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — binding partner identified with functional consequence validated by knockdown and recombinant protein rescue in elastogenesis assay\",\n      \"pmids\": [\"17581631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LOXL1 interacts with FBLN5, which in turn engages αvβ3 integrin in an RGD domain-dependent manner to activate the FAK-MAPK signaling pathway inside vascular endothelial cells, promoting angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, RGD domain mutation, in vitro and in vivo proliferation/metastasis assays\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and domain-mutation demonstrating RGD-dependent integrin engagement with downstream FAK-MAPK activation\",\n      \"pmids\": [\"33614230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-200c directly targets the 3' UTR of FBLN5 mRNA and represses its expression, as validated by luciferase reporter assay.\",\n      \"method\": \"Luciferase reporter assay with 3' UTR, gain-of-function miR-200c transfection\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3' UTR luciferase validation of miR-200c targeting FBLN5, single lab\",\n      \"pmids\": [\"22685266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-370-3p directly targets FBLN5, inhibiting its expression and activating the NF-κB signaling pathway to promote breast cancer cell proliferation, migration, and stemness.\",\n      \"method\": \"Luciferase reporter assay, overexpression/knockdown of miR-370-3p, western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3' UTR luciferase reporter validation, functional rescue experiments, single lab\",\n      \"pmids\": [\"34475958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-27a-3p negatively regulates FBLN5 by directly binding to its 3' UTR, as shown by dual-luciferase reporter assay; FBLN5 overexpression inhibits migration, invasion, and proliferation of ovarian cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, overexpression functional assays (migration, invasion, proliferation)\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3' UTR validation plus functional overexpression phenotype, single lab\",\n      \"pmids\": [\"32901854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NDUFS1 reduction leads to activation of mitochondrial ROS-HIF1α signaling, which transcriptionally upregulates FBLN5 expression in gastric cancer cells, identifying FBLN5 as a transcriptional target of HIF1α downstream of mROS.\",\n      \"method\": \"Western blot, confocal microscopy, knockdown/overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement of FBLN5 as HIF1α transcriptional target via mROS signaling, single lab\",\n      \"pmids\": [\"37644092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A heterozygous mutation (c.1117C>T) in FBLN5 causes adult-onset demyelinating neuropathy (autosomal dominant Charcot-Marie-Tooth disease type 1), demonstrating FBLN5's role in peripheral nerve maintenance.\",\n      \"method\": \"Genetic sequencing, nerve biopsy (histopathology), nerve conduction velocity studies\",\n      \"journal\": \"Clinical neuropathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutation identified with neuropathological validation by biopsy, but mechanistic link to FBLN5 function not fully resolved\",\n      \"pmids\": [\"28332470\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBLN5 (fibulin-5/DANCE/EVEC) is a secreted extracellular matrix glycoprotein that functions as an elastogenic organizer by depositing on fibrillin-1 microfibrils, promoting tropoelastin coacervation and alignment, and tethering lysyl oxidase-like enzymes (LOXL1/2/4) to crosslink tropoelastin into mature elastic fibers; it also mediates cell adhesion and signaling through RGD-dependent binding to integrins (αvβ3, αvβ5, α9β1) to activate FAK-MAPK pathways, is induced by TGF-β through a Smad3-independent mechanism to modulate ERK and p38 MAPK activity, and is regulated post-transcriptionally by multiple miRNAs (miR-200c, miR-27a-3p, miR-370-3p) targeting its 3' UTR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBLN5 is a secreted extracellular matrix glycoprotein that serves as the central organizer of elastic fiber assembly and mediates integrin-dependent cell signaling in vascular, dermal, and pulmonary tissues. It deposits on fibrillin-1 microfibrils—guided by LTBP-2—to promote tropoelastin coacervation and tethers lysyl oxidase-like enzymes (LOXL1/2/4) for tropoelastin crosslinking into mature elastic fibers [PMID:17371835, PMID:17581631]. Through its RGD motif, FBLN5 binds integrins (αvβ3, αvβ5, α9β1) to activate FAK-MAPK signaling, and its expression is induced by TGF-β via a Smad3-independent pathway and transcriptionally regulated by HIF1α downstream of mitochondrial ROS [PMID:10428823, PMID:12021267, PMID:33614230, PMID:37644092]. Loss-of-function mutations in FBLN5 cause autosomal recessive cutis laxa, and a heterozygous FBLN5 mutation has been identified in autosomal dominant demyelinating neuropathy [PMID:12189163, PMID:28332470].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that FBLN5 is a secreted ECM protein with an RGD-integrin cell-adhesion function resolved the question of how this novel fibulin family member mediates cell-matrix interactions.\",\n      \"evidence\": \"Recombinant FBLN5 protein expression and cell adhesion assays demonstrating RGD-dependent integrin binding\",\n      \"pmids\": [\"10428823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific integrin receptor subtypes not fully defined\", \"Downstream intracellular signaling from integrin engagement not characterized\", \"In vivo adhesion function not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that FBLN5 is highly expressed in developing arteries and re-induced after vascular injury established it as a dynamically regulated vascular ECM component rather than a constitutive structural protein.\",\n      \"evidence\": \"In situ hybridization and subtraction hybridization in mouse vascular tissues\",\n      \"pmids\": [\"10347091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of re-induction after injury not tested\", \"Transcriptional regulators of FBLN5 in vascular development unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linking TGF-β to FBLN5 induction via a Smad3-independent route and showing that FBLN5 amplifies ERK and p38 MAPK signaling revealed FBLN5 as both a target and modulator of growth factor pathways.\",\n      \"evidence\": \"Overexpression, dominant-negative constructs, and kinase assays in 3T3-L1 fibroblasts\",\n      \"pmids\": [\"12021267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the Smad3-independent TGF-β signaling intermediate unknown\", \"Whether MAPK amplification requires integrin engagement not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of a homozygous S227P mutation causing autosomal recessive cutis laxa directly linked FBLN5 to human elastogenesis and elastic tissue disease.\",\n      \"evidence\": \"Genetic mapping and Sanger sequencing in affected families\",\n      \"pmids\": [\"12189163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which S227P disrupts FBLN5 function not determined biochemically\", \"No rescue experiment performed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that a tandem duplication adding extra EGF-like domains also causes cutis laxa established that the precise domain architecture of FBLN5 is essential for elastogenic function.\",\n      \"evidence\": \"mRNA and protein analysis of mutant FBLN5 from an affected individual\",\n      \"pmids\": [\"12618961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the mutant protein acts in a dominant-negative fashion or is simply nonfunctional was not resolved\", \"Elastogenesis assay with the duplicated protein not performed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reconstitution experiments established FBLN5 as the elastogenic organizer by showing it deposits on fibrillin-1 microfibrils, promotes tropoelastin coacervation, and tethers LOXL1/2/4 for crosslinking—resolving how elastic fiber assembly is coordinated.\",\n      \"evidence\": \"Recombinant FBLN5 elastogenesis assays, knockdown, co-localization and binding assays with LOXL enzymes in cultured cells\",\n      \"pmids\": [\"17371835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FBLN5–LOXL interaction not determined\", \"Whether age-related truncated FBLN5 actively inhibits elastogenesis or is merely inactive not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying LTBP-2 as a physical binding partner that targets FBLN5 onto fibrillin-1 microfibrils explained how FBLN5 is spatially directed during elastic fiber assembly.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown of LTBP-2, and recombinant rescue in human skin fibroblasts\",\n      \"pmids\": [\"17581631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between LTBP-2 and FBLN5 not mapped\", \"In vivo validation of LTBP-2 requirement for FBLN5 microfibrillar deposition not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A heterozygous FBLN5 mutation causing autosomal dominant demyelinating neuropathy extended FBLN5's disease spectrum beyond elastic tissue disorders to peripheral nerve maintenance.\",\n      \"evidence\": \"Genetic sequencing with nerve biopsy and conduction studies in an affected family\",\n      \"pmids\": [\"28332470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FBLN5 mutation leads to demyelination is unknown\", \"Not independently replicated in additional families\", \"No functional assay of mutant protein in nerve tissue\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that LOXL1–FBLN5–αvβ3 integrin forms a signaling axis activating FAK-MAPK in endothelial cells linked the elastogenic scaffold function of FBLN5 to intracellular pro-angiogenic signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, RGD domain mutation, knockdown/overexpression in vascular endothelial cells with in vitro and in vivo functional assays\",\n      \"pmids\": [\"33614230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FAK-MAPK activation is independent of elastic fiber context not resolved\", \"Stoichiometry and direct vs. indirect nature of the ternary complex unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placement of FBLN5 as a transcriptional target of HIF1α downstream of mitochondrial ROS revealed an oxygen-sensing transcriptional input for FBLN5 regulation in cancer.\",\n      \"evidence\": \"Knockdown/overexpression of NDUFS1, Western blot, confocal microscopy in gastric cancer cells\",\n      \"pmids\": [\"37644092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF1α binding to FBLN5 promoter not shown by ChIP\", \"Relevance of this axis to normal elastic tissue homeostasis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of FBLN5 interactions with tropoelastin, LOXL enzymes, and LTBP-2 remains unresolved, and the mechanism by which FBLN5 mutations cause demyelinating neuropathy is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of FBLN5 or its complexes\", \"Mechanism of FBLN5 in peripheral nerve maintenance entirely uncharacterized\", \"Whether age-related truncation of FBLN5 is a regulated process or a degradation artifact is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 4, 7, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LOXL1\", \"LOXL2\", \"LOXL4\", \"LTBP2\", \"FBN1\", \"ITGAV\", \"ITGB3\"],\n    \"other_free_text\": []\n  }\n}\n```"}