{"gene":"FBLN5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1999,"finding":"FBLN5 (DANCE) is a secreted extracellular matrix protein that promotes adhesion of endothelial cells through interaction of integrins with its RGD motif, identifying it as a vascular ligand for integrin receptors.","method":"Overexpression of recombinant DANCE protein; cell adhesion assays; in situ hybridization","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein overexpression and functional cell adhesion assay in single study, single lab","pmids":["10428823"],"is_preprint":false},{"year":1999,"finding":"FBLN5 (EVEC) mRNA is expressed predominantly in vascular smooth muscle cells of developing arteries and is reactivated in balloon-injured vessels and atherosclerotic lesions, suggesting a role in vascular growth and remodeling.","method":"In situ hybridization; subtraction hybridization cloning; expression in rodent vascular injury models","journal":"Circulation Research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in situ hybridization localization in two independent rodent injury models, single lab","pmids":["10347091"],"is_preprint":false},{"year":2002,"finding":"FBLN5 is an integrin-binding extracellular matrix protein that also functions as a calcium-dependent elastin-binding protein, scaffolding cells to elastic fibers and preventing elastinopathy in skin, lung, and vasculature.","method":"Recombinant protein binding assays; cell adhesion assays; overexpression in multiple cell lines","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical binding characterization and functional cell assays in single study","pmids":["12021267"],"is_preprint":false},{"year":2002,"finding":"TGF-β stimulates fibroblasts to synthesize FBLN5 transcript and protein through a Smad3-independent pathway, and FBLN5 overexpression enhances basal and TGF-β-stimulated activation of ERK1/ERK2 and p38 MAPK.","method":"Dominant-negative Smad3 overexpression; ERK1/ERK2 and p38 MAPK activation assays; DNA synthesis assays","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via dominant-negative constructs and kinase activation assays, single lab","pmids":["12021267"],"is_preprint":false},{"year":2002,"finding":"FBLN5 overexpression synergizes with TGF-β to stimulate AP-1 activity, an effect abrogated by dominant-negative MKK1 or p38 MAPKα, placing FBLN5 upstream of MKK1/ERK and p38 MAPK pathways.","method":"AP-1 reporter assays; dominant-negative MKK1 and p38 MAPKα overexpression; kinase activation assays","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via dominant-negative constructs, single lab, two orthogonal readouts","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 type I in humans, demonstrating that FBLN5 function is required for normal elastogenesis in skin, lung, and vasculature.","method":"Genetic mutation identification in consanguineous family; structural prediction of domain disruption","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human genetics with structural prediction; consistent with knockout mouse phenotype from other studies","pmids":["12189163"],"is_preprint":false},{"year":2003,"finding":"A heterozygous tandem duplication within FBLN5 producing a mutant protein with four additional calcium-binding EGF-like motifs causes autosomal dominant cutis laxa, indicating that altered FBLN5 protein structure disrupts elastogenesis.","method":"mRNA transcript analysis; gene duplication mapping; detection of secreted mutant protein","journal":"American Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein synthesis and secretion confirmed, single lab, genetic and biochemical characterization","pmids":["12618961"],"is_preprint":false},{"year":2003,"finding":"FBLN5 mRNA and protein are coordinately expressed and regulated with elastin in lung fibroblasts; fibulin-5 protein is localized to the fibroblast cell layer and is susceptible to elastase degradation; interleukin-1β abolishes FBLN5 mRNA expression.","method":"Northern analysis; immunohistochemistry; Western blot; elastase treatment of cultured fibroblasts; cytokine treatment","journal":"American Journal of Physiology - Lung Cellular and Molecular Physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple complementary methods in single study, cell fractionation and protein localization with functional consequence","pmids":["12909585"],"is_preprint":false},{"year":2007,"finding":"FBLN5 acts as an elastogenic organizer by promoting coacervation and alignment of tropoelastin on microfibrils and tethering lysyl oxidase-like (LOXL) 1, 2, and 4 enzymes to facilitate tropoelastin crosslinking; truncated FBLN5 (increasing with age) cannot promote elastogenesis.","method":"Recombinant FBLN5 protein elastogenesis assay in serum-free conditions; co-localization of LOXL enzymes; biochemical characterization of full-length vs. truncated FBLN5","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of elastogenesis with recombinant protein, multiple orthogonal methods, functional validation with truncation mutant","pmids":["17371835"],"is_preprint":false},{"year":2007,"finding":"LTBP-2 binds directly to FBLN5 (DANCE) and regulates elastic fiber assembly: LTBP-2 downregulation induces fibrillin-1-independent fibrillar deposition of FBLN5 and elastin, and recombinant LTBP-2 promotes deposition of FBLN5 onto fibrillin-1 microfibrils.","method":"Co-immunoprecipitation (identification of LTBP-2 as DANCE-binding protein); siRNA knockdown of LTBP-2; elastogenesis assays in human skin fibroblasts; recombinant protein addition","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — binding partner identification with Co-IP, functional validation by knockdown and recombinant protein rescue, multiple orthogonal methods in single study","pmids":["17581631"],"is_preprint":false},{"year":2021,"finding":"LOXL1 interacts physically with FBLN5, and FBLN5 binds αvβ3 integrin in an RGD domain-dependent manner to activate the FAK-MAPK signaling pathway in vascular endothelial cells, promoting angiogenesis.","method":"Co-immunoprecipitation of LOXL1 and FBLN5; RGD-dependent binding assays; FAK-MAPK pathway activation assays; overexpression and depletion experiments in ICC cell lines","journal":"Molecular Therapy - Nucleic Acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pathway activation assays, single lab, multiple methods","pmids":["33614230"],"is_preprint":false},{"year":2021,"finding":"miR-370-3p directly targets the 3'UTR of FBLN5 to inhibit its expression, and this inhibition activates the NF-κB signaling pathway to promote breast cancer cell proliferation, migration, and stemness.","method":"3'UTR luciferase reporter assay; miR-370-3p overexpression and FBLN5 knockdown; NF-κB pathway activation assays; in vivo xenograft","journal":"Stem Cells International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter validation and downstream pathway assays, single lab","pmids":["34475958"],"is_preprint":false},{"year":2023,"finding":"NDUFS1 reduction upregulates FBLN5 expression as a transcriptional target of HIF1α through activation of the mitochondrial ROS-HIF1α signaling pathway in gastric cancer cells.","method":"Western blot; confocal microscopy for subcellular localization; overexpression/knockdown experiments; ROS measurement; in vivo xenograft","journal":"British Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis via loss-of-function and pathway inhibition, single lab, multiple orthogonal methods","pmids":["37644092"],"is_preprint":false},{"year":2021,"finding":"FBLN5 is a direct target of miR-138; miR-138 inhibition in bone marrow-derived mesenchymal stem cells increases FBLN5 expression, elevates elastin secretion, and downregulates IL-1β, improving pelvic floor function in a rat prolapse model.","method":"Target identification by miR-138 inhibition; RT-qPCR and western blot for FBLN5, elastin, IL-1β; functional in vivo assays (leak point pressure, cystometry)","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation with functional readouts in vitro and in vivo, single lab","pmids":["33460398"],"is_preprint":false},{"year":2022,"finding":"UBE2T knockdown increases FBLN5 expression and inhibits activation of p-ERK, p-GSK3β, and β-catenin in lung adenocarcinoma cells; FBLN5 knockdown partially reverses the anti-proliferative and anti-migratory effects of UBE2T silencing, placing FBLN5 downstream of UBE2T.","method":"shRNA knockdown; ChIP; EMSA; GST pull-down; CCK-8/transwell assays; xenograft mouse model","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double knockdown, biochemical binding assays (GST pull-down, ChIP), single lab","pmids":["35543375"],"is_preprint":false},{"year":2012,"finding":"miR-200c directly targets the 3'UTR of FBLN5 to repress its expression, as validated by luciferase reporter assay; miR-200c gain-of-function in leiomyoma and myometrial smooth muscle cells inhibits proliferation.","method":"3'UTR luciferase reporter assay; miR-200c gain-of-function experiments; proliferation assays","journal":"Endocrine-Related Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter validation with functional assays, single lab","pmids":["22685266"],"is_preprint":false}],"current_model":"FBLN5 (fibulin-5/DANCE/EVEC) is a secreted extracellular matrix glycoprotein that acts as an elastogenic organizer by binding tropoelastin, tethering lysyl oxidase-like enzymes (LOXL1/2/4) to microfibrils to drive tropoelastin crosslinking, and interacting with LTBP-2 to regulate targeting onto fibrillin-1 microfibrils; it also functions as an RGD-containing integrin ligand (αvβ3, αvβ5, α9β1) that activates FAK-MAPK and, in a context-dependent manner, ERK1/2, p38 MAPK, and NF-κB signaling pathways, while its expression is regulated by TGF-β (via a Smad3-independent pathway), HIF1α (downstream of mitochondrial ROS), and multiple miRNAs (miR-200c, miR-370-3p, miR-138) that directly target its 3'UTR."},"narrative":{"mechanistic_narrative":"FBLN5 (fibulin-5/DANCE/EVEC) is a secreted, calcium-dependent extracellular matrix glycoprotein that serves as a central organizer of elastic fiber assembly while also functioning as an integrin ligand that couples the matrix to intracellular signaling [PMID:12021267, PMID:17371835]. As an elastogenic scaffold, FBLN5 promotes coacervation and alignment of tropoelastin on microfibrils and tethers the lysyl oxidase-like enzymes LOXL1, LOXL2, and LOXL4 to drive tropoelastin crosslinking; age-associated truncated FBLN5 loses this elastogenic capacity [PMID:17371835]. Its deposition onto fibrillin-1 microfibrils is regulated through direct binding to LTBP-2, which controls whether FBLN5 and elastin assemble in a fibrillin-1-dependent or -independent manner [PMID:17581631]. Through its RGD motif, FBLN5 engages integrins (including αvβ3) to mediate cell adhesion and activate FAK-MAPK signaling, and its overexpression potentiates ERK1/2, p38 MAPK, and AP-1 activity downstream of TGF-β via a Smad3-independent route [PMID:10428823, PMID:12021267, PMID:33614230]. The requirement for FBLN5 in human elastogenesis is established genetically: a homozygous S227P missense mutation in its fourth calcium-binding EGF-like domain causes autosomal recessive cutis laxa type I, and a heterozygous tandem duplication adding EGF-like motifs causes autosomal dominant cutis laxa [PMID:12189163, PMID:12618961]. FBLN5 expression is regulated by TGF-β and IL-1β, by HIF1α downstream of mitochondrial ROS, and by multiple microRNAs (miR-200c, miR-370-3p, miR-138) that directly target its 3'UTR, linking its levels to proliferation, migration, and NF-κB signaling in cancer and smooth muscle contexts [PMID:12021267, PMID:12909585, PMID:34475958, PMID:37644092, PMID:22685266].","teleology":[{"year":1999,"claim":"Established FBLN5 as a secreted vascular ECM protein and integrin ligand, answering whether it had a cell-interactive function rather than being purely structural.","evidence":"Recombinant DANCE protein in endothelial cell adhesion assays plus in situ hybridization in developing and injured vasculature","pmids":["10428823","10347091"],"confidence":"Medium","gaps":["Which specific integrin heterodimers engage the RGD motif was not resolved","Downstream signaling consequences of adhesion not defined"]},{"year":2002,"claim":"Defined FBLN5 as a dual elastin- and integrin-binding protein and placed it upstream of MAPK signaling, connecting matrix scaffolding to intracellular pathways.","evidence":"Recombinant calcium-dependent elastin-binding assays, cell adhesion assays, and ERK1/2, p38, and AP-1 activation epistasis using dominant-negative Smad3, MKK1, and p38α","pmids":["12021267"],"confidence":"Medium","gaps":["Mechanistic link between integrin engagement and MAPK activation not directly demonstrated","Smad3-independent TGF-β transcriptional mechanism not identified"]},{"year":2002,"claim":"Demonstrated that FBLN5 function is genetically required for human elastogenesis, moving it from a candidate elastic-fiber protein to a disease gene.","evidence":"Homozygous S227P missense mutation in a calcium-binding EGF-like domain identified in a consanguineous cutis laxa family; heterozygous EGF-domain duplication in dominant cutis laxa","pmids":["12189163","12618961"],"confidence":"Medium","gaps":["How the specific domain alterations disrupt elastogenesis biochemically was inferred from structure, not measured","Genotype-phenotype basis for recessive vs dominant inheritance not mechanistically resolved"]},{"year":2003,"claim":"Showed FBLN5 is coordinately co-regulated with elastin and is susceptible to elastase, linking its abundance to elastic fiber turnover and inflammation.","evidence":"Northern, Western, and immunohistochemistry in lung fibroblasts with elastase and IL-1β treatment","pmids":["12909585"],"confidence":"Medium","gaps":["Transcriptional regulators mediating co-regulation with elastin not identified","Functional consequence of elastase cleavage products not tested"]},{"year":2007,"claim":"Reconstituted the core elastogenic mechanism, showing FBLN5 organizes tropoelastin on microfibrils and recruits LOXL enzymes for crosslinking, and is integrated onto fibrillin-1 via LTBP-2.","evidence":"In vitro elastogenesis assay with recombinant full-length vs truncated FBLN5 and LOXL co-localization; Co-IP identifying LTBP-2, with siRNA knockdown and recombinant rescue in skin fibroblasts","pmids":["17371835","17581631"],"confidence":"High","gaps":["Stoichiometry and structural basis of the FBLN5-tropoelastin-LOXL assembly not resolved","How LTBP-2 binding switches deposition modes mechanistically unclear"]},{"year":2021,"claim":"Connected the elastogenic and signaling roles in a tumor context, showing LOXL1-FBLN5 physical interaction and RGD-dependent αvβ3 integrin engagement activating FAK-MAPK to drive angiogenesis.","evidence":"Reciprocal Co-IP, RGD-dependent binding, and FAK-MAPK activation assays with overexpression/depletion in cholangiocarcinoma cells","pmids":["33614230"],"confidence":"Medium","gaps":["Whether LOXL1 binding and integrin signaling are mechanistically coupled not shown","Generalizability beyond the cancer cell context not tested"]},{"year":2012,"claim":"Identified post-transcriptional control of FBLN5 by microRNAs, establishing that its expression is tunable and linking it to proliferative phenotypes.","evidence":"3'UTR luciferase reporter assays and gain/loss-of-function with miR-200c, miR-370-3p, and miR-138 across smooth muscle, cancer, and stem cell models","pmids":["22685266","34475958","33460398"],"confidence":"Medium","gaps":["Relative contribution of each miRNA in physiological tissue not established","Whether FBLN5 repression by miRNAs acts through elastogenesis or signaling differs by context"]},{"year":2023,"claim":"Placed FBLN5 in a regulatory network downstream of transcriptional and signaling inputs, identifying HIF1α and UBE2T-linked pathways controlling its expression.","evidence":"Loss-of-function of NDUFS1 with ROS measurement and HIF1α epistasis in gastric cancer; UBE2T knockdown with ChIP/EMSA/GST pull-down and double-knockdown rescue in lung adenocarcinoma","pmids":["37644092","35543375"],"confidence":"Medium","gaps":["Direct HIF1α occupancy of the FBLN5 promoter vs indirect regulation not fully separated","How FBLN5 mediates downstream ERK/GSK3β/β-catenin effects mechanistically unclear"]},{"year":null,"claim":"How FBLN5's distinct roles as an elastogenic scaffold versus an integrin-signaling ligand are coordinated within a single tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the FBLN5-tropoelastin-LOXL-LTBP2 assembly","Whether signaling and elastogenic functions use the same or separable protein interfaces is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["LOXL1","LOXL2","LOXL4","LTBP2","ITGAV","ITGB3","TROPOELASTIN"],"other_free_text":[]}},"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":1194,"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":243,"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":199,"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":"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":147,"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":"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":145,"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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cell adhesion assays; in situ hybridization\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein overexpression and functional cell adhesion assay in single study, single lab\",\n      \"pmids\": [\"10428823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FBLN5 (EVEC) mRNA is expressed predominantly in vascular smooth muscle cells of developing arteries and is reactivated in balloon-injured vessels and atherosclerotic lesions, suggesting a role in vascular growth and remodeling.\",\n      \"method\": \"In situ hybridization; subtraction hybridization cloning; expression in rodent vascular injury models\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in situ hybridization localization in two independent rodent injury models, single lab\",\n      \"pmids\": [\"10347091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FBLN5 is an integrin-binding extracellular matrix protein that also functions as a calcium-dependent elastin-binding protein, scaffolding cells to elastic fibers and preventing elastinopathy in skin, lung, and vasculature.\",\n      \"method\": \"Recombinant protein binding assays; cell adhesion assays; overexpression in multiple cell lines\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding characterization and functional cell assays in single study\",\n      \"pmids\": [\"12021267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TGF-β stimulates fibroblasts to synthesize FBLN5 transcript and protein through a Smad3-independent pathway, and FBLN5 overexpression enhances basal and TGF-β-stimulated activation of ERK1/ERK2 and p38 MAPK.\",\n      \"method\": \"Dominant-negative Smad3 overexpression; ERK1/ERK2 and p38 MAPK activation assays; DNA synthesis assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via dominant-negative constructs and kinase activation assays, single lab\",\n      \"pmids\": [\"12021267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FBLN5 overexpression synergizes with TGF-β to stimulate AP-1 activity, an effect abrogated by dominant-negative MKK1 or p38 MAPKα, placing FBLN5 upstream of MKK1/ERK and p38 MAPK pathways.\",\n      \"method\": \"AP-1 reporter assays; dominant-negative MKK1 and p38 MAPKα overexpression; kinase activation assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via dominant-negative constructs, single lab, two orthogonal readouts\",\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 type I in humans, demonstrating that FBLN5 function is required for normal elastogenesis in skin, lung, and vasculature.\",\n      \"method\": \"Genetic mutation identification in consanguineous family; structural prediction of domain disruption\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human genetics with structural prediction; consistent with knockout mouse phenotype from other studies\",\n      \"pmids\": [\"12189163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A heterozygous tandem duplication within FBLN5 producing a mutant protein with four additional calcium-binding EGF-like motifs causes autosomal dominant cutis laxa, indicating that altered FBLN5 protein structure disrupts elastogenesis.\",\n      \"method\": \"mRNA transcript analysis; gene duplication mapping; detection of secreted mutant protein\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein synthesis and secretion confirmed, single lab, genetic and biochemical characterization\",\n      \"pmids\": [\"12618961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FBLN5 mRNA and protein are coordinately expressed and regulated with elastin in lung fibroblasts; fibulin-5 protein is localized to the fibroblast cell layer and is susceptible to elastase degradation; interleukin-1β abolishes FBLN5 mRNA expression.\",\n      \"method\": \"Northern analysis; immunohistochemistry; Western blot; elastase treatment of cultured fibroblasts; cytokine treatment\",\n      \"journal\": \"American Journal of Physiology - Lung Cellular and Molecular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple complementary methods in single study, cell fractionation and protein localization with functional consequence\",\n      \"pmids\": [\"12909585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FBLN5 acts as an elastogenic organizer by promoting coacervation and alignment of tropoelastin on microfibrils and tethering lysyl oxidase-like (LOXL) 1, 2, and 4 enzymes to facilitate tropoelastin crosslinking; truncated FBLN5 (increasing with age) cannot promote elastogenesis.\",\n      \"method\": \"Recombinant FBLN5 protein elastogenesis assay in serum-free conditions; co-localization of LOXL enzymes; biochemical characterization of full-length vs. truncated FBLN5\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of elastogenesis with recombinant protein, multiple orthogonal methods, functional validation with truncation mutant\",\n      \"pmids\": [\"17371835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LTBP-2 binds directly to FBLN5 (DANCE) and regulates elastic fiber assembly: LTBP-2 downregulation induces fibrillin-1-independent fibrillar deposition of FBLN5 and elastin, and recombinant LTBP-2 promotes deposition of FBLN5 onto fibrillin-1 microfibrils.\",\n      \"method\": \"Co-immunoprecipitation (identification of LTBP-2 as DANCE-binding protein); siRNA knockdown of LTBP-2; elastogenesis assays in human skin fibroblasts; recombinant protein addition\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — binding partner identification with Co-IP, functional validation by knockdown and recombinant protein rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17581631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LOXL1 interacts physically with FBLN5, and FBLN5 binds αvβ3 integrin in an RGD domain-dependent manner to activate the FAK-MAPK signaling pathway in vascular endothelial cells, promoting angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation of LOXL1 and FBLN5; RGD-dependent binding assays; FAK-MAPK pathway activation assays; overexpression and depletion experiments in ICC cell lines\",\n      \"journal\": \"Molecular Therapy - Nucleic Acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pathway activation assays, single lab, multiple methods\",\n      \"pmids\": [\"33614230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-370-3p directly targets the 3'UTR of FBLN5 to inhibit its expression, and this inhibition activates the NF-κB signaling pathway to promote breast cancer cell proliferation, migration, and stemness.\",\n      \"method\": \"3'UTR luciferase reporter assay; miR-370-3p overexpression and FBLN5 knockdown; NF-κB pathway activation assays; in vivo xenograft\",\n      \"journal\": \"Stem Cells International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter validation and downstream pathway assays, single lab\",\n      \"pmids\": [\"34475958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NDUFS1 reduction upregulates FBLN5 expression as a transcriptional target of HIF1α through activation of the mitochondrial ROS-HIF1α signaling pathway in gastric cancer cells.\",\n      \"method\": \"Western blot; confocal microscopy for subcellular localization; overexpression/knockdown experiments; ROS measurement; in vivo xenograft\",\n      \"journal\": \"British Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis via loss-of-function and pathway inhibition, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37644092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBLN5 is a direct target of miR-138; miR-138 inhibition in bone marrow-derived mesenchymal stem cells increases FBLN5 expression, elevates elastin secretion, and downregulates IL-1β, improving pelvic floor function in a rat prolapse model.\",\n      \"method\": \"Target identification by miR-138 inhibition; RT-qPCR and western blot for FBLN5, elastin, IL-1β; functional in vivo assays (leak point pressure, cystometry)\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation with functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"33460398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE2T knockdown increases FBLN5 expression and inhibits activation of p-ERK, p-GSK3β, and β-catenin in lung adenocarcinoma cells; FBLN5 knockdown partially reverses the anti-proliferative and anti-migratory effects of UBE2T silencing, placing FBLN5 downstream of UBE2T.\",\n      \"method\": \"shRNA knockdown; ChIP; EMSA; GST pull-down; CCK-8/transwell assays; xenograft mouse model\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double knockdown, biochemical binding assays (GST pull-down, ChIP), single lab\",\n      \"pmids\": [\"35543375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-200c directly targets the 3'UTR of FBLN5 to repress its expression, as validated by luciferase reporter assay; miR-200c gain-of-function in leiomyoma and myometrial smooth muscle cells inhibits proliferation.\",\n      \"method\": \"3'UTR luciferase reporter assay; miR-200c gain-of-function experiments; proliferation assays\",\n      \"journal\": \"Endocrine-Related Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter validation with functional assays, single lab\",\n      \"pmids\": [\"22685266\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBLN5 (fibulin-5/DANCE/EVEC) is a secreted extracellular matrix glycoprotein that acts as an elastogenic organizer by binding tropoelastin, tethering lysyl oxidase-like enzymes (LOXL1/2/4) to microfibrils to drive tropoelastin crosslinking, and interacting with LTBP-2 to regulate targeting onto fibrillin-1 microfibrils; it also functions as an RGD-containing integrin ligand (αvβ3, αvβ5, α9β1) that activates FAK-MAPK and, in a context-dependent manner, ERK1/2, p38 MAPK, and NF-κB signaling pathways, while its expression is regulated by TGF-β (via a Smad3-independent pathway), HIF1α (downstream of mitochondrial ROS), and multiple miRNAs (miR-200c, miR-370-3p, miR-138) that directly target its 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBLN5 (fibulin-5/DANCE/EVEC) is a secreted, calcium-dependent extracellular matrix glycoprotein that serves as a central organizer of elastic fiber assembly while also functioning as an integrin ligand that couples the matrix to intracellular signaling [#2, #8]. As an elastogenic scaffold, FBLN5 promotes coacervation and alignment of tropoelastin on microfibrils and tethers the lysyl oxidase-like enzymes LOXL1, LOXL2, and LOXL4 to drive tropoelastin crosslinking; age-associated truncated FBLN5 loses this elastogenic capacity [#8]. Its deposition onto fibrillin-1 microfibrils is regulated through direct binding to LTBP-2, which controls whether FBLN5 and elastin assemble in a fibrillin-1-dependent or -independent manner [#9]. Through its RGD motif, FBLN5 engages integrins (including \\u03b1v\\u03b23) to mediate cell adhesion and activate FAK-MAPK signaling, and its overexpression potentiates ERK1/2, p38 MAPK, and AP-1 activity downstream of TGF-\\u03b2 via a Smad3-independent route [#0, #3, #4, #10]. The requirement for FBLN5 in human elastogenesis is established genetically: a homozygous S227P missense mutation in its fourth calcium-binding EGF-like domain causes autosomal recessive cutis laxa type I, and a heterozygous tandem duplication adding EGF-like motifs causes autosomal dominant cutis laxa [#5, #6]. FBLN5 expression is regulated by TGF-\\u03b2 and IL-1\\u03b2, by HIF1\\u03b1 downstream of mitochondrial ROS, and by multiple microRNAs (miR-200c, miR-370-3p, miR-138) that directly target its 3'UTR, linking its levels to proliferation, migration, and NF-\\u03baB signaling in cancer and smooth muscle contexts [#3, #7, #11, #12, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established FBLN5 as a secreted vascular ECM protein and integrin ligand, answering whether it had a cell-interactive function rather than being purely structural.\",\n      \"evidence\": \"Recombinant DANCE protein in endothelial cell adhesion assays plus in situ hybridization in developing and injured vasculature\",\n      \"pmids\": [\"10428823\", \"10347091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific integrin heterodimers engage the RGD motif was not resolved\", \"Downstream signaling consequences of adhesion not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined FBLN5 as a dual elastin- and integrin-binding protein and placed it upstream of MAPK signaling, connecting matrix scaffolding to intracellular pathways.\",\n      \"evidence\": \"Recombinant calcium-dependent elastin-binding assays, cell adhesion assays, and ERK1/2, p38, and AP-1 activation epistasis using dominant-negative Smad3, MKK1, and p38\\u03b1\",\n      \"pmids\": [\"12021267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between integrin engagement and MAPK activation not directly demonstrated\", \"Smad3-independent TGF-\\u03b2 transcriptional mechanism not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that FBLN5 function is genetically required for human elastogenesis, moving it from a candidate elastic-fiber protein to a disease gene.\",\n      \"evidence\": \"Homozygous S227P missense mutation in a calcium-binding EGF-like domain identified in a consanguineous cutis laxa family; heterozygous EGF-domain duplication in dominant cutis laxa\",\n      \"pmids\": [\"12189163\", \"12618961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the specific domain alterations disrupt elastogenesis biochemically was inferred from structure, not measured\", \"Genotype-phenotype basis for recessive vs dominant inheritance not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed FBLN5 is coordinately co-regulated with elastin and is susceptible to elastase, linking its abundance to elastic fiber turnover and inflammation.\",\n      \"evidence\": \"Northern, Western, and immunohistochemistry in lung fibroblasts with elastase and IL-1\\u03b2 treatment\",\n      \"pmids\": [\"12909585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional regulators mediating co-regulation with elastin not identified\", \"Functional consequence of elastase cleavage products not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reconstituted the core elastogenic mechanism, showing FBLN5 organizes tropoelastin on microfibrils and recruits LOXL enzymes for crosslinking, and is integrated onto fibrillin-1 via LTBP-2.\",\n      \"evidence\": \"In vitro elastogenesis assay with recombinant full-length vs truncated FBLN5 and LOXL co-localization; Co-IP identifying LTBP-2, with siRNA knockdown and recombinant rescue in skin fibroblasts\",\n      \"pmids\": [\"17371835\", \"17581631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the FBLN5-tropoelastin-LOXL assembly not resolved\", \"How LTBP-2 binding switches deposition modes mechanistically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected the elastogenic and signaling roles in a tumor context, showing LOXL1-FBLN5 physical interaction and RGD-dependent \\u03b1v\\u03b23 integrin engagement activating FAK-MAPK to drive angiogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, RGD-dependent binding, and FAK-MAPK activation assays with overexpression/depletion in cholangiocarcinoma cells\",\n      \"pmids\": [\"33614230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LOXL1 binding and integrin signaling are mechanistically coupled not shown\", \"Generalizability beyond the cancer cell context not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified post-transcriptional control of FBLN5 by microRNAs, establishing that its expression is tunable and linking it to proliferative phenotypes.\",\n      \"evidence\": \"3'UTR luciferase reporter assays and gain/loss-of-function with miR-200c, miR-370-3p, and miR-138 across smooth muscle, cancer, and stem cell models\",\n      \"pmids\": [\"22685266\", \"34475958\", \"33460398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each miRNA in physiological tissue not established\", \"Whether FBLN5 repression by miRNAs acts through elastogenesis or signaling differs by context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed FBLN5 in a regulatory network downstream of transcriptional and signaling inputs, identifying HIF1\\u03b1 and UBE2T-linked pathways controlling its expression.\",\n      \"evidence\": \"Loss-of-function of NDUFS1 with ROS measurement and HIF1\\u03b1 epistasis in gastric cancer; UBE2T knockdown with ChIP/EMSA/GST pull-down and double-knockdown rescue in lung adenocarcinoma\",\n      \"pmids\": [\"37644092\", \"35543375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF1\\u03b1 occupancy of the FBLN5 promoter vs indirect regulation not fully separated\", \"How FBLN5 mediates downstream ERK/GSK3\\u03b2/\\u03b2-catenin effects mechanistically unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FBLN5's distinct roles as an elastogenic scaffold versus an integrin-signaling ligand are coordinated within a single tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the FBLN5-tropoelastin-LOXL-LTBP2 assembly\", \"Whether signaling and elastogenic functions use the same or separable protein interfaces is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LOXL1\", \"LOXL2\", \"LOXL4\", \"LTBP2\", \"ITGAV\", \"ITGB3\", \"tropoelastin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}