{"gene":"FBLN2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1994,"finding":"Fibulin-2 protein domain architecture was characterized: the mature protein contains two N-terminal subdomains (cysteine-rich Na and cysteine-free Nb), three anaphylatoxin-related segments (domain I), 10 EGF-like repeats with calcium-binding consensus sequences (domain II), and a C-terminal fibulin-type module (domain III). The gene was localized to human chromosome 3p24-p25.","method":"Human cDNA cloning, sequencing, Northern blot, in situ hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — primary sequence/structural characterization with multiple orthogonal methods in foundational study","pmids":["7806230"],"is_preprint":false},{"year":2018,"finding":"miR-192-5p directly targets the 3'-UTR of Fbln2 mRNA (validated by dual-luciferase reporter assay), suppressing Fbln2 expression and thereby inhibiting TGF-β1 signaling pathway activation; elevated Fbln2 activates TGF-β1 signaling in a mouse depression model.","method":"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, siRNA knockdown, behavioral and electrophysiological assays in CUMS mouse model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — dual-luciferase validation plus functional rescue, single lab","pmids":["30118321"],"is_preprint":false},{"year":2021,"finding":"Enteric neuron-secreted Fbln2 (released upon Ndrg4 loss) enhances migration of colorectal cancer cells; Fbln2 is expressed in enteric neurons and enriched in the Ndrg4-/- secretome.","method":"Ndrg4 knockout mouse models, indirect co-culture of enteric nervous system cells with intestinal organoids, quantitative proteomics of secretome, immunostaining, migration assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus functional migration assay with genetic KO, single lab","pmids":["33890711"],"is_preprint":false},{"year":2021,"finding":"GAS5 lncRNA sponges miR-128-3p to upregulate FBLN2 expression; miR-128-3p directly targets FBLN2 (validated by dual-luciferase reporter and RIP assays), and this axis regulates proliferation and apoptosis in ox-LDL-treated THP-1 macrophages.","method":"Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), CCK-8 proliferation assay, flow cytometry apoptosis assay, qRT-PCR, western blot","journal":"Clinical hemorheology and microcirculation","confidence":"Medium","confidence_rationale":"Tier 2 — dual-luciferase and RIP validation with functional readouts, single lab","pmids":["33074219"],"is_preprint":false},{"year":2022,"finding":"FBLN2 physically binds vitronectin (VTN) and negatively regulates VTN expression; FBLN2 knockdown attenuates TGF-β1-induced fibrosis, migration, and MMP2/MMP9 expression in MRC-5 lung fibroblasts via suppression of FAK signaling, and VTN overexpression rescues these inhibitory effects.","method":"Co-immunoprecipitation, siRNA knockdown, western blot, wound healing assay, immunofluorescence, CCK-8 assay","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2/3 — co-IP binding plus functional rescue experiment, single lab","pmids":["36608640"],"is_preprint":false},{"year":2022,"finding":"Fbln2 is a marker of a highly profibrotic hepatic stellate cell (HSC) subpopulation (Lrat+Fbln2+) that expands dramatically in alcoholic hepatitis; this subpopulation shows elevated profibrotic, myofibroblastic, and immunoregulatory gene expression compared to Lrat+Fbln2- HSCs, identified by lineage tracing in Lrat-Cre;Rosa26mTmG mice.","method":"Single-cell RNA sequencing, FACS sorting, HSC lineage tracing (Lrat-Cre;Rosa26mTmG), immunohistochemistry, in situ hybridization, computational deconvolution of bulk RNA-seq","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq plus genetic lineage tracing with multiple orthogonal validations, single lab","pmids":["36181700"],"is_preprint":false},{"year":2024,"finding":"FBLN2 knockdown in mouse mammary epithelial cells reduces KRT14 (basal marker) and increases KRT18 (luminal marker) expression; TGFβ3 treatment upregulates FBLN2, indicating FBLN2 is required for basement membrane integrity and myoepithelial phenotype maintenance.","method":"siRNA knockdown, TGFβ3 treatment, immunocytochemistry, immunoblotting in EpH4 cells and pubertal mouse mammary glands","journal":"Breast cancer research and treatment","confidence":"Low","confidence_rationale":"Tier 3 — single lab, knockdown with marker readout, no mechanistic pathway validated","pmids":["39110274"],"is_preprint":false},{"year":2024,"finding":"ITGBL1 promotes anoikis resistance and metastasis in gastric cancer through AKT-mediated suppression of FBLN2; inhibition of AKT/FBLN2 signaling reverses ITGBL1-driven anoikis resistance and metastasis.","method":"Overexpression and knockdown of ITGBL1, AKT inhibition, in vitro anoikis and metastasis assays, in vivo tumor models","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain/loss-of-function with pathway inhibitor rescue in vitro and in vivo, single lab","pmids":["38332530"],"is_preprint":false},{"year":2024,"finding":"fbln2 knockout in zebrafish causes craniofacial malformations with abnormal chondrocyte morphology, defective chondrogenic differentiation, increased apoptosis and altered proliferation of cranial neural crest cells (CNCCs), and downregulation of BMP signaling; fbln2 is specifically expressed in the mandible during early zebrafish development.","method":"CRISPR/Cas9 knockout, whole-exome sequencing linkage analysis, in situ hybridization, histology, cell proliferation/apoptosis assays, BMP pathway analysis in zebrafish","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype and pathway placement in vertebrate model organism","pmids":["38970771"],"is_preprint":false},{"year":2024,"finding":"circ_0001944 sponges miR-1292-5p, which directly targets the 3'-UTR of FBLN2 mRNA (validated by RIP, RNA pulldown, dual-luciferase assay); this circ_0001944/miR-1292-5p/FBLN2 axis inhibits ferroptosis (iron overload and lipid peroxidation regulators) to promote sorafenib resistance in hepatocellular carcinoma.","method":"RNA-seq, RNA binding protein immunoprecipitation (RIP), RNA pull-down, dual-luciferase reporter assay, iron detection, lipid peroxidation assay, ROS measurement, in vivo tumor models","journal":"ImmunoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal RNA interaction validations with functional ferroptosis assays, single lab","pmids":["39624827"],"is_preprint":false},{"year":2025,"finding":"Alternative splicing of FBLN2 exon 9 exclusion removes a single N-glycosylation site, causing protein misfolding, reduced stability, and reduced secretion efficiency; the resulting deficiency of extracellular FBLN2 together with increased fibronectin 1 promotes adhesion and migration of colorectal cancer cells.","method":"RNA-seq splicing analysis, cancer tissue proteomics, glycosylation site mutagenesis, protein stability/secretion assays, cell adhesion and migration assays","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of glycosylation site with biochemical validation of misfolding/secretion and functional cell assays","pmids":["40400104"],"is_preprint":false},{"year":2025,"finding":"FBLN2 overexpression reduces gastric cancer cell proliferation and metastasis, while FBLN2 knockout enhances them; mechanistically, FBLN2 suppresses GC progression by downregulating the TGFβ/TGIF2 axis, as determined by RNA-seq and KEGG analysis of FBLN2 knockout vs. wild-type GC cells.","method":"FBLN2 overexpression and knockout in GC cells, in vitro and in vivo proliferation/metastasis assays, RNA-seq with KEGG pathway enrichment analysis","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain/loss-of-function with transcriptomic pathway placement in vitro and in vivo, single lab","pmids":["40168772"],"is_preprint":false},{"year":2026,"finding":"In zebrafish heart regeneration, Fbln2 regulates epicardial cell activation; Fbln2 attenuation stimulates regenerative programs. Nupr1b was identified as an Fbln2 effector that controls epicardial myofibroblast abundance; epicardial-specific overexpression of nupr1b rescued fbln2 mutant cardiac regeneration phenotypes, placing Fbln2 upstream of Nupr1b in epicardial cell state transitions after injury.","method":"Genetic tools for Fbln2 dosage (gain- and loss-of-function), zebrafish cardiac injury model, epicardial-specific Nupr1b overexpression, epistasis rescue experiments","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple gain/loss-of-function tools and defined rescue in a vertebrate model organism","pmids":["41776059"],"is_preprint":false},{"year":2023,"finding":"FBLN2 participates in early osteogenic differentiation of mesenchymal stem cells (MSCs); FBLN2 knockdown during osteogenic differentiation alters protein expression profiles associated with biological regulation and stimulus-response pathways, as determined by quantitative proteomics.","method":"TMT-based quantitative proteomics, siRNA knockdown, osteogenic differentiation assay, GO and network analysis","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 — single lab, proteomics-based pathway inference without direct mechanistic validation","pmids":["37543430"],"is_preprint":false}],"current_model":"FBLN2 is a secreted extracellular matrix glycoprotein with a multi-domain architecture (anaphylatoxin repeats, EGF-like repeats, fibulin C-terminal module) whose glycosylation state (determined by alternative splicing of exon 9) controls its folding, stability, and secretion; it acts as an upstream regulator of multiple signaling pathways including TGF-β/TGIF2, BMP, and AKT/FAK axes — binding partners include vitronectin — and functions in diverse cellular processes such as epicardial cell state transitions (via a Fbln2-Nupr1b effector axis), cranial neural crest cell development (through BMP signaling), myofibroblast regulation, and suppression of cancer cell migration and anoikis resistance."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing the molecular identity of FBLN2 resolved the domain architecture of this extracellular matrix protein, revealing a modular structure of anaphylatoxin repeats, calcium-binding EGF-like repeats, and a fibulin C-terminal module that implied diverse binding capabilities.","evidence":"Human cDNA cloning, sequencing, Northern blot, and chromosomal mapping to 3p24-p25","pmids":["7806230"],"confidence":"High","gaps":["No binding partners identified at this stage","No functional role established","Protein tertiary structure not determined"]},{"year":2018,"claim":"Demonstrating that Fbln2 activates TGF-β1 signaling — and is itself post-transcriptionally regulated by miR-192-5p — established the first signaling pathway placement for FBLN2 as an upstream activator of TGF-β1.","evidence":"Dual-luciferase reporter assay validating miR-192-5p targeting of Fbln2 3′-UTR, siRNA knockdown with TGF-β1 pathway readouts in CUMS mouse model","pmids":["30118321"],"confidence":"Medium","gaps":["Mechanism by which FBLN2 activates TGF-β1 signaling not resolved","Single disease context (depression model)","No direct FBLN2–TGF-β1 receptor interaction shown"]},{"year":2021,"claim":"Identifying FBLN2 as a neuron-secreted factor that enhances cancer cell migration revealed a paracrine role for FBLN2 in the tumor microenvironment and linked its secretion to Ndrg4 loss in enteric neurons.","evidence":"Ndrg4 knockout mouse, secretome proteomics, indirect co-culture migration assays with intestinal organoids","pmids":["33890711"],"confidence":"Medium","gaps":["Receptor or adhesion molecule mediating FBLN2-driven migration not identified","No direct FBLN2 gain-of-function in neurons tested"]},{"year":2022,"claim":"Demonstrating that FBLN2 physically binds vitronectin and suppresses FAK signaling provided the first direct binding partner and a downstream effector pathway for FBLN2 in fibrotic responses.","evidence":"Co-immunoprecipitation of FBLN2–vitronectin, siRNA knockdown with VTN rescue in TGF-β1-treated MRC-5 lung fibroblasts","pmids":["36608640"],"confidence":"Medium","gaps":["Binding domain on FBLN2 for vitronectin not mapped","Reciprocal co-IP not explicitly described","Single cell type tested"]},{"year":2022,"claim":"Single-cell profiling established Fbln2 as a marker of a profibrotic, myofibroblastic hepatic stellate cell subpopulation that expands in alcoholic hepatitis, positioning FBLN2 in liver fibrosis biology.","evidence":"scRNA-seq, FACS, Lrat-Cre lineage tracing in mouse models of alcoholic hepatitis","pmids":["36181700"],"confidence":"Medium","gaps":["Whether FBLN2 is functionally required for the profibrotic phenotype or merely a marker is untested","No FBLN2 loss-of-function in HSCs"]},{"year":2024,"claim":"Genetic knockout of fbln2 in zebrafish revealed its requirement for BMP-dependent cranial neural crest chondrogenesis, establishing a developmental function and connecting FBLN2 to BMP signaling.","evidence":"CRISPR/Cas9 fbln2 knockout in zebrafish with craniofacial phenotyping, BMP pathway analysis, proliferation and apoptosis assays","pmids":["38970771"],"confidence":"Medium","gaps":["Mechanism by which FBLN2 activates BMP signaling unknown","Whether this role is conserved in mammals not tested"]},{"year":2024,"claim":"Placing FBLN2 downstream of AKT in gastric cancer anoikis resistance — where ITGBL1 suppresses FBLN2 via AKT — established FBLN2 as a tumor-suppressive effector whose loss confers anchorage-independent survival.","evidence":"ITGBL1 overexpression/knockdown with AKT inhibitor rescue, in vitro anoikis assays and in vivo tumor models","pmids":["38332530"],"confidence":"Medium","gaps":["Direct molecular mechanism of AKT-mediated FBLN2 suppression unclear (transcriptional vs. post-translational)","Single cancer type"]},{"year":2025,"claim":"Demonstrating that alternative splicing of exon 9 removes an N-glycosylation site essential for FBLN2 folding, stability, and secretion resolved a post-translational mechanism controlling extracellular FBLN2 availability and its tumor-suppressive function in colorectal cancer.","evidence":"Glycosylation site mutagenesis, protein stability and secretion assays, cell adhesion and migration assays in colorectal cancer cells","pmids":["40400104"],"confidence":"High","gaps":["Splicing regulators controlling exon 9 inclusion not identified","Whether this mechanism operates in non-cancer tissues unknown"]},{"year":2025,"claim":"Genetic gain- and loss-of-function studies showed FBLN2 suppresses gastric cancer via the TGFβ/TGIF2 axis, converging with earlier TGF-β pathway placement and solidifying FBLN2 as a tumor suppressor.","evidence":"FBLN2 overexpression and CRISPR knockout in GC cells, RNA-seq pathway analysis, in vivo xenograft models","pmids":["40168772"],"confidence":"Medium","gaps":["Mechanism by which FBLN2 downregulates TGIF2 not dissected","Whether FBLN2 acts extracellularly or intracellularly on this axis unresolved"]},{"year":2026,"claim":"Epistasis experiments in zebrafish cardiac regeneration identified Nupr1b as a downstream effector of Fbln2 in epicardial cell state transitions, establishing a Fbln2–Nupr1b axis governing myofibroblast abundance during heart repair.","evidence":"Fbln2 gain/loss-of-function, epicardial-specific Nupr1b overexpression rescue in zebrafish cardiac injury model","pmids":["41776059"],"confidence":"High","gaps":["Intermediate signaling steps between FBLN2 and Nupr1b activation unknown","Mammalian conservation of this axis not demonstrated"]},{"year":null,"claim":"The receptor(s) and cell-surface signaling complexes through which secreted FBLN2 activates or modulates TGF-β, BMP, and other pathways remain unidentified, as does a high-resolution structural model of the protein.","evidence":"","pmids":[],"confidence":"High","gaps":["No FBLN2 receptor identified","No crystal or cryo-EM structure available","Splicing regulators of exon 9 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,7,8,11,12]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,7,8,11]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,12]}],"complexes":[],"partners":["VTN","NUPR1B","TGIF2","ITGBL1","FN1"],"other_free_text":[]},"mechanistic_narrative":"FBLN2 encodes a secreted extracellular matrix glycoprotein whose multi-domain architecture — comprising anaphylatoxin-related segments, calcium-binding EGF-like repeats, and a C-terminal fibulin-type module — enables it to function as a signaling scaffold that modulates TGF-β, BMP, and AKT/FAK pathways in diverse developmental and disease contexts [PMID:7806230, PMID:30118321, PMID:38970771, PMID:40168772]. Alternative splicing of exon 9 controls an N-glycosylation site critical for proper folding, stability, and secretion; loss of this glycosylation produces misfolded protein that accumulates intracellularly, reducing extracellular FBLN2 and promoting colorectal cancer cell adhesion and migration [PMID:40400104]. FBLN2 binds vitronectin and negatively regulates its expression, suppressing FAK-mediated fibrotic and migratory responses in fibroblasts, and acts as a tumor suppressor in gastric cancer by downregulating the TGFβ/TGIF2 axis and conferring anoikis sensitivity [PMID:36608640, PMID:40168772, PMID:38332530]. In zebrafish, Fbln2 is required for BMP-dependent cranial neural crest chondrogenesis and regulates epicardial cell state transitions during cardiac regeneration through a Fbln2–Nupr1b effector axis [PMID:38970771, PMID:41776059]."},"prefetch_data":{"uniprot":{"accession":"P98095","full_name":"Fibulin-2","aliases":[],"length_aa":1184,"mass_kda":126.6,"function":"Its binding to fibronectin and some other ligands is calcium dependent. May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/P98095/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBLN2","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/FBLN2","total_profiled":1310},"omim":[{"mim_id":"610168","title":"LOEYS-DIETZ SYNDROME 2; LDS2","url":"https://www.omim.org/entry/610168"},{"mim_id":"606217","title":"ATRIOVENTRICULAR SEPTAL DEFECT, SUSCEPTIBILITY TO, 2; AVSD2","url":"https://www.omim.org/entry/606217"},{"mim_id":"606215","title":"ATRIOVENTRICULAR SEPTAL DEFECT; AVSD","url":"https://www.omim.org/entry/606215"},{"mim_id":"605399","title":"NIDOGEN 2; NID2","url":"https://www.omim.org/entry/605399"},{"mim_id":"605083","title":"FRIZZLED-RELATED PROTEIN; FRZB","url":"https://www.omim.org/entry/605083"}],"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":"heart muscle","ntpm":287.6}],"url":"https://www.proteinatlas.org/search/FBLN2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P98095","domains":[{"cath_id":"-","chopping":"41-114","consensus_level":"medium","plddt":81.0532,"start":41,"end":114},{"cath_id":"-","chopping":"440-501_514-555","consensus_level":"medium","plddt":83.9356,"start":440,"end":555},{"cath_id":"2.10.25.10","chopping":"683-728","consensus_level":"medium","plddt":79.8572,"start":683,"end":728},{"cath_id":"-","chopping":"762-792","consensus_level":"medium","plddt":79.6577,"start":762,"end":792},{"cath_id":"2.60.40.60","chopping":"1066-1181","consensus_level":"high","plddt":89.7899,"start":1066,"end":1181}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98095","model_url":"https://alphafold.ebi.ac.uk/files/AF-P98095-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P98095-F1-predicted_aligned_error_v6.png","plddt_mean":67.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBLN2","jax_strain_url":"https://www.jax.org/strain/search?query=FBLN2"},"sequence":{"accession":"P98095","fasta_url":"https://rest.uniprot.org/uniprotkb/P98095.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98095/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98095"}},"corpus_meta":[{"pmid":"33971972","id":"PMC_33971972","title":"Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH.","date":"2021","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33971972","citation_count":69,"is_preprint":false},{"pmid":"7806230","id":"PMC_7806230","title":"Fibulin-2 (FBLN2): human cDNA sequence, mRNA expression, and mapping of the gene on human and mouse chromosomes.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7806230","citation_count":47,"is_preprint":false},{"pmid":"30118321","id":"PMC_30118321","title":"Up-regulated miR-192-5p expression rescues cognitive impairment and restores neural function in mice with depression via the Fbln2-mediated TGF-β1 signaling pathway.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30118321","citation_count":40,"is_preprint":false},{"pmid":"33890711","id":"PMC_33890711","title":"Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33890711","citation_count":31,"is_preprint":false},{"pmid":"36608640","id":"PMC_36608640","title":"Knockdown of FBLN2 suppresses TGF-β1-induced MRC-5 cell migration and fibrosis by downregulating VTN.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/36608640","citation_count":17,"is_preprint":false},{"pmid":"39110274","id":"PMC_39110274","title":"FBLN2 is associated with basal cell markers Krt14 and ITGB1 in mouse mammary epithelial cells and has a preferential expression in molecular subtypes of human breast cancer.","date":"2024","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/39110274","citation_count":13,"is_preprint":false},{"pmid":"38332530","id":"PMC_38332530","title":"ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38332530","citation_count":11,"is_preprint":false},{"pmid":"36181700","id":"PMC_36181700","title":"Emergence of highly profibrotic and proinflammatory Lrat+Fbln2+ HSC subpopulation in alcoholic hepatitis.","date":"2022","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/36181700","citation_count":9,"is_preprint":false},{"pmid":"38970771","id":"PMC_38970771","title":"FBLN2 is associated with Goldenhar syndrome and is essential for cranial neural crest cell development.","date":"2024","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38970771","citation_count":8,"is_preprint":false},{"pmid":"33074219","id":"PMC_33074219","title":"Long non-coding RNA GAS5 knockdown facilitates proliferation and impedes apoptosis by regulating miR-128-3p/FBLN2 axis in ox-LDL-induced THP-1 cells.","date":"2021","source":"Clinical hemorheology and microcirculation","url":"https://pubmed.ncbi.nlm.nih.gov/33074219","citation_count":7,"is_preprint":false},{"pmid":"37543430","id":"PMC_37543430","title":"TMT-based quantitative proteomic analysis revealed that FBLN2 and NPR3 are involved in the early osteogenic differentiation of mesenchymal stem cells (MSCs).","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37543430","citation_count":5,"is_preprint":false},{"pmid":"39624827","id":"PMC_39624827","title":"Circ_0001944 Targets the miR-1292-5p/FBLN2 Axis to Facilitate Sorafenib Resistance in Hepatocellular Carcinoma by Impeding Ferroptosis.","date":"2024","source":"ImmunoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39624827","citation_count":4,"is_preprint":false},{"pmid":"40168772","id":"PMC_40168772","title":"FBLN2 inhibits gastric cancer proliferation and metastasis via the TGFβ/TGIF2 pathway.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/40168772","citation_count":1,"is_preprint":false},{"pmid":"40400104","id":"PMC_40400104","title":"Alternative Splicing of FBLN2 Generates a Prometastatic Extracellular Matrix in Gastrointestinal Cancers by Determining N-Glycosylation of Fibulin 2.","date":"2025","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40400104","citation_count":1,"is_preprint":false},{"pmid":"41776059","id":"PMC_41776059","title":"Attenuation of epicardial activation and myofibroblast abundance via the Fbln2-Nupr1b axis stimulates cardiac regeneration in zebrafish.","date":"2026","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/41776059","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10310,"output_tokens":3462,"usd":0.04143},"stage2":{"model":"claude-opus-4-6","input_tokens":6869,"output_tokens":2692,"usd":0.152468},"total_usd":0.193898,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Fibulin-2 protein domain architecture was characterized: the mature protein contains two N-terminal subdomains (cysteine-rich Na and cysteine-free Nb), three anaphylatoxin-related segments (domain I), 10 EGF-like repeats with calcium-binding consensus sequences (domain II), and a C-terminal fibulin-type module (domain III). The gene was localized to human chromosome 3p24-p25.\",\n      \"method\": \"Human cDNA cloning, sequencing, Northern blot, in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary sequence/structural characterization with multiple orthogonal methods in foundational study\",\n      \"pmids\": [\"7806230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-192-5p directly targets the 3'-UTR of Fbln2 mRNA (validated by dual-luciferase reporter assay), suppressing Fbln2 expression and thereby inhibiting TGF-β1 signaling pathway activation; elevated Fbln2 activates TGF-β1 signaling in a mouse depression model.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, siRNA knockdown, behavioral and electrophysiological assays in CUMS mouse model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual-luciferase validation plus functional rescue, single lab\",\n      \"pmids\": [\"30118321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Enteric neuron-secreted Fbln2 (released upon Ndrg4 loss) enhances migration of colorectal cancer cells; Fbln2 is expressed in enteric neurons and enriched in the Ndrg4-/- secretome.\",\n      \"method\": \"Ndrg4 knockout mouse models, indirect co-culture of enteric nervous system cells with intestinal organoids, quantitative proteomics of secretome, immunostaining, migration assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus functional migration assay with genetic KO, single lab\",\n      \"pmids\": [\"33890711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GAS5 lncRNA sponges miR-128-3p to upregulate FBLN2 expression; miR-128-3p directly targets FBLN2 (validated by dual-luciferase reporter and RIP assays), and this axis regulates proliferation and apoptosis in ox-LDL-treated THP-1 macrophages.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), CCK-8 proliferation assay, flow cytometry apoptosis assay, qRT-PCR, western blot\",\n      \"journal\": \"Clinical hemorheology and microcirculation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual-luciferase and RIP validation with functional readouts, single lab\",\n      \"pmids\": [\"33074219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBLN2 physically binds vitronectin (VTN) and negatively regulates VTN expression; FBLN2 knockdown attenuates TGF-β1-induced fibrosis, migration, and MMP2/MMP9 expression in MRC-5 lung fibroblasts via suppression of FAK signaling, and VTN overexpression rescues these inhibitory effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blot, wound healing assay, immunofluorescence, CCK-8 assay\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP binding plus functional rescue experiment, single lab\",\n      \"pmids\": [\"36608640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fbln2 is a marker of a highly profibrotic hepatic stellate cell (HSC) subpopulation (Lrat+Fbln2+) that expands dramatically in alcoholic hepatitis; this subpopulation shows elevated profibrotic, myofibroblastic, and immunoregulatory gene expression compared to Lrat+Fbln2- HSCs, identified by lineage tracing in Lrat-Cre;Rosa26mTmG mice.\",\n      \"method\": \"Single-cell RNA sequencing, FACS sorting, HSC lineage tracing (Lrat-Cre;Rosa26mTmG), immunohistochemistry, in situ hybridization, computational deconvolution of bulk RNA-seq\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq plus genetic lineage tracing with multiple orthogonal validations, single lab\",\n      \"pmids\": [\"36181700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBLN2 knockdown in mouse mammary epithelial cells reduces KRT14 (basal marker) and increases KRT18 (luminal marker) expression; TGFβ3 treatment upregulates FBLN2, indicating FBLN2 is required for basement membrane integrity and myoepithelial phenotype maintenance.\",\n      \"method\": \"siRNA knockdown, TGFβ3 treatment, immunocytochemistry, immunoblotting in EpH4 cells and pubertal mouse mammary glands\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown with marker readout, no mechanistic pathway validated\",\n      \"pmids\": [\"39110274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGBL1 promotes anoikis resistance and metastasis in gastric cancer through AKT-mediated suppression of FBLN2; inhibition of AKT/FBLN2 signaling reverses ITGBL1-driven anoikis resistance and metastasis.\",\n      \"method\": \"Overexpression and knockdown of ITGBL1, AKT inhibition, in vitro anoikis and metastasis assays, in vivo tumor models\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain/loss-of-function with pathway inhibitor rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"38332530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"fbln2 knockout in zebrafish causes craniofacial malformations with abnormal chondrocyte morphology, defective chondrogenic differentiation, increased apoptosis and altered proliferation of cranial neural crest cells (CNCCs), and downregulation of BMP signaling; fbln2 is specifically expressed in the mandible during early zebrafish development.\",\n      \"method\": \"CRISPR/Cas9 knockout, whole-exome sequencing linkage analysis, in situ hybridization, histology, cell proliferation/apoptosis assays, BMP pathway analysis in zebrafish\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype and pathway placement in vertebrate model organism\",\n      \"pmids\": [\"38970771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circ_0001944 sponges miR-1292-5p, which directly targets the 3'-UTR of FBLN2 mRNA (validated by RIP, RNA pulldown, dual-luciferase assay); this circ_0001944/miR-1292-5p/FBLN2 axis inhibits ferroptosis (iron overload and lipid peroxidation regulators) to promote sorafenib resistance in hepatocellular carcinoma.\",\n      \"method\": \"RNA-seq, RNA binding protein immunoprecipitation (RIP), RNA pull-down, dual-luciferase reporter assay, iron detection, lipid peroxidation assay, ROS measurement, in vivo tumor models\",\n      \"journal\": \"ImmunoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal RNA interaction validations with functional ferroptosis assays, single lab\",\n      \"pmids\": [\"39624827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Alternative splicing of FBLN2 exon 9 exclusion removes a single N-glycosylation site, causing protein misfolding, reduced stability, and reduced secretion efficiency; the resulting deficiency of extracellular FBLN2 together with increased fibronectin 1 promotes adhesion and migration of colorectal cancer cells.\",\n      \"method\": \"RNA-seq splicing analysis, cancer tissue proteomics, glycosylation site mutagenesis, protein stability/secretion assays, cell adhesion and migration assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of glycosylation site with biochemical validation of misfolding/secretion and functional cell assays\",\n      \"pmids\": [\"40400104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBLN2 overexpression reduces gastric cancer cell proliferation and metastasis, while FBLN2 knockout enhances them; mechanistically, FBLN2 suppresses GC progression by downregulating the TGFβ/TGIF2 axis, as determined by RNA-seq and KEGG analysis of FBLN2 knockout vs. wild-type GC cells.\",\n      \"method\": \"FBLN2 overexpression and knockout in GC cells, in vitro and in vivo proliferation/metastasis assays, RNA-seq with KEGG pathway enrichment analysis\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain/loss-of-function with transcriptomic pathway placement in vitro and in vivo, single lab\",\n      \"pmids\": [\"40168772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In zebrafish heart regeneration, Fbln2 regulates epicardial cell activation; Fbln2 attenuation stimulates regenerative programs. Nupr1b was identified as an Fbln2 effector that controls epicardial myofibroblast abundance; epicardial-specific overexpression of nupr1b rescued fbln2 mutant cardiac regeneration phenotypes, placing Fbln2 upstream of Nupr1b in epicardial cell state transitions after injury.\",\n      \"method\": \"Genetic tools for Fbln2 dosage (gain- and loss-of-function), zebrafish cardiac injury model, epicardial-specific Nupr1b overexpression, epistasis rescue experiments\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple gain/loss-of-function tools and defined rescue in a vertebrate model organism\",\n      \"pmids\": [\"41776059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBLN2 participates in early osteogenic differentiation of mesenchymal stem cells (MSCs); FBLN2 knockdown during osteogenic differentiation alters protein expression profiles associated with biological regulation and stimulus-response pathways, as determined by quantitative proteomics.\",\n      \"method\": \"TMT-based quantitative proteomics, siRNA knockdown, osteogenic differentiation assay, GO and network analysis\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, proteomics-based pathway inference without direct mechanistic validation\",\n      \"pmids\": [\"37543430\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBLN2 is a secreted extracellular matrix glycoprotein with a multi-domain architecture (anaphylatoxin repeats, EGF-like repeats, fibulin C-terminal module) whose glycosylation state (determined by alternative splicing of exon 9) controls its folding, stability, and secretion; it acts as an upstream regulator of multiple signaling pathways including TGF-β/TGIF2, BMP, and AKT/FAK axes — binding partners include vitronectin — and functions in diverse cellular processes such as epicardial cell state transitions (via a Fbln2-Nupr1b effector axis), cranial neural crest cell development (through BMP signaling), myofibroblast regulation, and suppression of cancer cell migration and anoikis resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBLN2 encodes a secreted extracellular matrix glycoprotein whose multi-domain architecture — comprising anaphylatoxin-related segments, calcium-binding EGF-like repeats, and a C-terminal fibulin-type module — enables it to function as a signaling scaffold that modulates TGF-β, BMP, and AKT/FAK pathways in diverse developmental and disease contexts [PMID:7806230, PMID:30118321, PMID:38970771, PMID:40168772]. Alternative splicing of exon 9 controls an N-glycosylation site critical for proper folding, stability, and secretion; loss of this glycosylation produces misfolded protein that accumulates intracellularly, reducing extracellular FBLN2 and promoting colorectal cancer cell adhesion and migration [PMID:40400104]. FBLN2 binds vitronectin and negatively regulates its expression, suppressing FAK-mediated fibrotic and migratory responses in fibroblasts, and acts as a tumor suppressor in gastric cancer by downregulating the TGFβ/TGIF2 axis and conferring anoikis sensitivity [PMID:36608640, PMID:40168772, PMID:38332530]. In zebrafish, Fbln2 is required for BMP-dependent cranial neural crest chondrogenesis and regulates epicardial cell state transitions during cardiac regeneration through a Fbln2–Nupr1b effector axis [PMID:38970771, PMID:41776059].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the molecular identity of FBLN2 resolved the domain architecture of this extracellular matrix protein, revealing a modular structure of anaphylatoxin repeats, calcium-binding EGF-like repeats, and a fibulin C-terminal module that implied diverse binding capabilities.\",\n      \"evidence\": \"Human cDNA cloning, sequencing, Northern blot, and chromosomal mapping to 3p24-p25\",\n      \"pmids\": [\"7806230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partners identified at this stage\", \"No functional role established\", \"Protein tertiary structure not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that Fbln2 activates TGF-β1 signaling — and is itself post-transcriptionally regulated by miR-192-5p — established the first signaling pathway placement for FBLN2 as an upstream activator of TGF-β1.\",\n      \"evidence\": \"Dual-luciferase reporter assay validating miR-192-5p targeting of Fbln2 3′-UTR, siRNA knockdown with TGF-β1 pathway readouts in CUMS mouse model\",\n      \"pmids\": [\"30118321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FBLN2 activates TGF-β1 signaling not resolved\", \"Single disease context (depression model)\", \"No direct FBLN2–TGF-β1 receptor interaction shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying FBLN2 as a neuron-secreted factor that enhances cancer cell migration revealed a paracrine role for FBLN2 in the tumor microenvironment and linked its secretion to Ndrg4 loss in enteric neurons.\",\n      \"evidence\": \"Ndrg4 knockout mouse, secretome proteomics, indirect co-culture migration assays with intestinal organoids\",\n      \"pmids\": [\"33890711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or adhesion molecule mediating FBLN2-driven migration not identified\", \"No direct FBLN2 gain-of-function in neurons tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that FBLN2 physically binds vitronectin and suppresses FAK signaling provided the first direct binding partner and a downstream effector pathway for FBLN2 in fibrotic responses.\",\n      \"evidence\": \"Co-immunoprecipitation of FBLN2–vitronectin, siRNA knockdown with VTN rescue in TGF-β1-treated MRC-5 lung fibroblasts\",\n      \"pmids\": [\"36608640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding domain on FBLN2 for vitronectin not mapped\", \"Reciprocal co-IP not explicitly described\", \"Single cell type tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Single-cell profiling established Fbln2 as a marker of a profibrotic, myofibroblastic hepatic stellate cell subpopulation that expands in alcoholic hepatitis, positioning FBLN2 in liver fibrosis biology.\",\n      \"evidence\": \"scRNA-seq, FACS, Lrat-Cre lineage tracing in mouse models of alcoholic hepatitis\",\n      \"pmids\": [\"36181700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBLN2 is functionally required for the profibrotic phenotype or merely a marker is untested\", \"No FBLN2 loss-of-function in HSCs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic knockout of fbln2 in zebrafish revealed its requirement for BMP-dependent cranial neural crest chondrogenesis, establishing a developmental function and connecting FBLN2 to BMP signaling.\",\n      \"evidence\": \"CRISPR/Cas9 fbln2 knockout in zebrafish with craniofacial phenotyping, BMP pathway analysis, proliferation and apoptosis assays\",\n      \"pmids\": [\"38970771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FBLN2 activates BMP signaling unknown\", \"Whether this role is conserved in mammals not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing FBLN2 downstream of AKT in gastric cancer anoikis resistance — where ITGBL1 suppresses FBLN2 via AKT — established FBLN2 as a tumor-suppressive effector whose loss confers anchorage-independent survival.\",\n      \"evidence\": \"ITGBL1 overexpression/knockdown with AKT inhibitor rescue, in vitro anoikis assays and in vivo tumor models\",\n      \"pmids\": [\"38332530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism of AKT-mediated FBLN2 suppression unclear (transcriptional vs. post-translational)\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that alternative splicing of exon 9 removes an N-glycosylation site essential for FBLN2 folding, stability, and secretion resolved a post-translational mechanism controlling extracellular FBLN2 availability and its tumor-suppressive function in colorectal cancer.\",\n      \"evidence\": \"Glycosylation site mutagenesis, protein stability and secretion assays, cell adhesion and migration assays in colorectal cancer cells\",\n      \"pmids\": [\"40400104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing regulators controlling exon 9 inclusion not identified\", \"Whether this mechanism operates in non-cancer tissues unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic gain- and loss-of-function studies showed FBLN2 suppresses gastric cancer via the TGFβ/TGIF2 axis, converging with earlier TGF-β pathway placement and solidifying FBLN2 as a tumor suppressor.\",\n      \"evidence\": \"FBLN2 overexpression and CRISPR knockout in GC cells, RNA-seq pathway analysis, in vivo xenograft models\",\n      \"pmids\": [\"40168772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FBLN2 downregulates TGIF2 not dissected\", \"Whether FBLN2 acts extracellularly or intracellularly on this axis unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Epistasis experiments in zebrafish cardiac regeneration identified Nupr1b as a downstream effector of Fbln2 in epicardial cell state transitions, establishing a Fbln2–Nupr1b axis governing myofibroblast abundance during heart repair.\",\n      \"evidence\": \"Fbln2 gain/loss-of-function, epicardial-specific Nupr1b overexpression rescue in zebrafish cardiac injury model\",\n      \"pmids\": [\"41776059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediate signaling steps between FBLN2 and Nupr1b activation unknown\", \"Mammalian conservation of this axis not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) and cell-surface signaling complexes through which secreted FBLN2 activates or modulates TGF-β, BMP, and other pathways remain unidentified, as does a high-resolution structural model of the protein.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No FBLN2 receptor identified\", \"No crystal or cryo-EM structure available\", \"Splicing regulators of exon 9 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 7, 8, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 7, 8, 11]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VTN\",\n      \"NUPR1B\",\n      \"TGIF2\",\n      \"ITGBL1\",\n      \"FN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}