{"gene":"FGFBP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2001,"finding":"Purified recombinant FGF-BP (FGFBP1) directly binds FGF-2 without additional cofactors, releases FGF-2 from the extracellular matrix, and stimulates tumor cell and endothelial cell proliferation and chemotaxis in a manner completely blocked by anti-FGF-2 antibodies, demonstrating that its paracrine growth-supporting effects are dependent on endogenously expressed FGF-2.","method":"In vitro binding assay with recombinant purified FGF-BP; cell proliferation and chemotaxis assays; antibody neutralization; immunodetection of high-molecular-weight FGF-BP complexes in xenografts","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified recombinant protein, antibody neutralization, and multiple functional readouts in a single study","pmids":["11304685"],"is_preprint":false},{"year":1998,"finding":"The heparin-binding site of FGFBP1 (HBp17) was mapped to residues 110–143 using protease digestion (V8 and chymotrypsin) followed by heparin-Sepharose isolation of binding fragments; a basic amino acid cluster in this region mediates binding to heparin/heparan sulfate proteoglycan.","method":"Protease peptide mapping; heparin-Sepharose affinity chromatography of peptide fragments","journal":"Biochemistry and molecular biology international","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct biochemical mapping with two proteases, single lab, no mutagenesis validation","pmids":["9784842"],"is_preprint":false},{"year":2001,"finding":"Serum induction of FGF-BP mRNA in squamous cell carcinoma cells is dependent on PKC, ERK kinase (MEK), and p38 MAP kinase activation, and the C/EBP promoter element is the main element required for this serum response; the mechanism differs from EGF-mediated induction (which uses AP-1 and E-box sites).","method":"Promoter analysis; kinase inhibitors; transcription run-on assay; site-directed mutagenesis of promoter elements","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion analysis combined with pharmacological pathway inhibition, single lab, two orthogonal methods","pmids":["11313920"],"is_preprint":false},{"year":2001,"finding":"HBp17 (FGFBP1) exhibits a biphasic dose-dependent effect on DNA synthesis: low concentrations (8 ng/ml) maximally stimulate DNA synthesis while high concentrations (~500 ng/ml) cause half-maximal inhibition, and this inhibition is reversed by addition of aFGF or bFGF but not EGF.","method":"DNA synthesis assay in 3T3 cells and HUVECs at varying HBp17 concentrations; FGF rescue experiment","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assay with defined dose-response and FGF rescue, single lab, single method","pmids":["11407864"],"is_preprint":false},{"year":2005,"finding":"Bovine FGF-BP (FGFBP1 ortholog, p37) purified from milk has higher binding affinity for bFGF than lactoferrin, serves as a phosphate acceptor for PKA, CK1, and CK2, and full phosphorylation by PKA abolishes its binding to lactoferrin in vitro; sulfatide-induced conformational changes enable CK1-mediated phosphorylation and also reduce lactoferrin binding.","method":"Heparin-HPLC purification; in vitro kinase assays (PKA, CK1, CK2); binding affinity assay; N-terminal sequencing","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical reconstitution with purified protein, multiple kinases tested, single lab","pmids":["16412577"],"is_preprint":false},{"year":2007,"finding":"N-terminal fragment p5 (residues 24–51) cleaved from FGF-BP in bovine milk is phosphorylated by PKA and CK1δ; CK1δ phosphorylation requires sulfated lipids (sulfatide or cholesterol-3-sulfate); a novel CK1δ phosphorylation site (RNRRGS) and SCS-binding site (RNRR) were identified; p5 (but not phosphorylated p5) directly binds aFGF.","method":"Gel filtration purification; in vitro kinase assays; immunoprecipitation; synthetic peptide analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical reconstitution with purified fragment and synthetic peptides, single lab","pmids":["17560725"],"is_preprint":false},{"year":2010,"finding":"Morpholino-mediated knockdown of Fgfbp1 in zebrafish causes massive cell death prominently in brain and neural tube, indicating that Fgfbp1 is essential for cellular survival during embryogenesis; this function appears to be at least partly FGF2-independent, as fgf2 morphants show a more severe and earlier phenotype.","method":"Morpholino knockdown in zebrafish embryos; cell death assay; comparison with fgf2 morphants","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with defined cellular phenotype and FGF2-independence inference, single lab","pmids":["20396962"],"is_preprint":false},{"year":2012,"finding":"1α,25(OH)2D3 downregulates HBp17/FGFBP1 mRNA and protein in oral squamous cell carcinoma cells via the NF-κB pathway (upregulating IκBα), and this effect requires vitamin D receptor (VDR); luciferase assay identified the responsive promoter region between −217 and +61.","method":"RT-PCR; Western blotting; luciferase reporter assay; VDR siRNA knockdown","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay plus siRNA confirmation plus mRNA/protein quantification, single lab, multiple orthogonal methods","pmids":["23104116"],"is_preprint":false},{"year":2014,"finding":"1α,25(OH)2D3 suppresses HBp17/FGFBP1 expression in both nucleus and cytosol of OSCC cells via NF-κB/VDR pathway, and this suppression results in reduced FGF-2 release into culture medium, establishing FGFBP1 as a chaperone required for FGF-2 secretion.","method":"Immunofluorescence; ELISA for FGF-2 in conditioned medium; pharmacological treatment","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (immunofluorescence localization + ELISA functional readout), single lab","pmids":["24938357"],"is_preprint":false},{"year":2016,"finding":"CREB3L1 suppresses FGFBP1 expression by binding to two CRE-like sites at approximately −1780 and −868 bp in the FGFBP1 promoter; miR-146a targets CREB3L1, thereby de-repressing FGFBP1 expression and increasing FGF2 secretion to promote angiogenesis in HUVECs.","method":"Luciferase reporter assay with FGFBP1 promoter; ChIP; CREB3L1 overexpression; FGF2 ELISA; lentiviral miR-146a overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter + ChIP + functional ELISA readout, single lab, multiple orthogonal methods","pmids":["27121396"],"is_preprint":false},{"year":2017,"finding":"Muscle fibers secrete and concentrate FGFBP1 at neuromuscular junctions (NMJs); FGFBP1 expression decreases before NMJ degeneration during aging and in SOD1G93A ALS mice; genetic deletion of FGFBP1 causes NMJ structural abnormalities and accelerates NMJ degeneration and death in SOD1G93A mice; TGF-β1 accumulation in stressed muscles inhibits FGFBP1 expression.","method":"FGFBP1 knockout mice; SOD1G93A mouse model; NMJ structural analysis; survival assay; TGF-β1 treatment","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific structural and survival phenotypes, disease model validation, TGF-β1 mechanism identified, multiple orthogonal experiments","pmids":["28053031"],"is_preprint":false},{"year":2017,"finding":"Inducible transgenic expression of FGFBP1 (BP1) in adult mice causes a sustained >30 mmHg rise in mean arterial blood pressure; this hypertensive effect is prevented by the AngII receptor antagonist candesartan or by the ROS inhibitor tempol; BP1 expression sensitizes peripheral resistance vessels and renal afferent arterioles to AngII constriction by ~20-fold via FGF receptor kinase-dependent signaling; AngII-mediated constriction is abolished in FGF2−/− mice but restored by FGF2 + BP1 add-back; MAPK signaling via MKK4, p38, and JNK integrates FGF receptor and AngII pathway crosstalk.","method":"Inducible transgenic mouse model; blood pressure telemetry; pharmacological inhibition (candesartan, tempol, FGFR kinase inhibitor); isolated vessel constriction assay; FGF2−/− mice with protein add-back; proteomics and gene expression analysis of kidney","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible transgenic model plus knockout rescue plus isolated vessel pharmacology plus multiple pathway validations in one rigorous study","pmids":["29158353"],"is_preprint":false},{"year":2019,"finding":"FGFBP1 is regulated by the FBW7/c-Myc axis in pancreatic cancer: FBW7 reduces FGFBP1 expression in a c-Myc-dependent manner; FGFBP1 silencing inhibits pancreatic cancer cell proliferation and metastasis, and FBW7 silencing partially reverses the effects of FGFBP1 silencing.","method":"siRNA knockdown; overexpression; co-expression correlation in patient tissue; epistasis rescue experiments in cell lines","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis via double knockdown/rescue experiments, single lab","pmids":["31911852"],"is_preprint":false},{"year":2020,"finding":"Endothelial genetic ablation of Fgfbp1 in mice causes transient hypervascularization, delays blood-brain barrier maturation (increased Plvap, increased tracer leakage) due to reduced Wnt/β-catenin activity, and reduces collagen IV deposition in the vascular basement membrane leading to defective pericyte interactions; Fgfbp1 acts cell-autonomously in brain endothelial cells to concentrate Wnt ligands near cell junctions.","method":"Endothelial-specific Fgfbp1 knockout mice; tracer leakage assay; immunostaining for Plvap and collagen IV; in vitro barrier assay with Wnt ligand localization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple orthogonal functional readouts (permeability, molecular markers, ECM composition, cell-cell interactions) in vivo and in vitro","pmids":["32747434"],"is_preprint":false},{"year":2020,"finding":"FGFBP1 mediates AKI-induced brain vascular sensitization to AngII: after bilateral renal ischemia-reperfusion injury, FGF2 and FGFBP1 are upregulated in serum and kidney; exogenous FGF2 + FGFBP1 proteins applied to healthy brain vessels mimic AKI-induced AngII sensitization; Fgfbp1−/− AKI mice fail to develop brain vascular AngII sensitization; FGFR kinase inhibition (BGJ398) reverses sensitization.","method":"Bilateral renal ischemia-reperfusion mouse model; Fgfbp1 knockout mice; isolated vessel constriction assay; protein add-back; FGFR inhibitor treatment","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout model plus protein add-back plus pharmacological inhibition across multiple orthogonal experiments, replicated mechanistic finding consistent with prior BP study","pmids":["33040621"],"is_preprint":false},{"year":2020,"finding":"HSD11B2 promotes colorectal cancer cell migration and invasion by upregulating FGFBP1 expression, which subsequently increases AKT phosphorylation; knockdown of either FGFBP1 or AKT impairs the migration/invasion promoted by HSD11B2 overexpression, placing FGFBP1 downstream of HSD11B2 in the HSD11B2-FGFBP1-AKT pathway.","method":"mRNA transcriptome array; overexpression and knockdown in CRC cell lines; in vitro migration/invasion assay; in vivo metastasis model; AKT phosphorylation Western blot","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via double knockdown and rescue, multiple orthogonal assays, single lab","pmids":["32195034"],"is_preprint":false},{"year":2021,"finding":"In pancreatic cancer, FGFBP1 expressed in cancer-associated fibroblasts (CAFs) promotes FGF22 release; FGF22 activates FGFR2 on pancreatic cancer cells to facilitate their invasion and metastasis; silencing FGFR2 in cancer cells blocks FGF22-driven invasion even with FGF22 treatment.","method":"Co-culture of CAFs with pancreatic cancer cells; FGFBP1 knockdown; ELISA for FGF22 in conditioned medium; siRNA knockdown of FGF22 and FGFR2; invasion assay","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ELISA plus co-culture functional assay plus receptor knockdown epistasis, single lab","pmids":["34117747"],"is_preprint":false},{"year":2021,"finding":"Poly-L-arginine (mimic of eosinophil major basic protein) induces FGFBP1 expression in airway epithelial cells via activation of the mTORC1-STAT3 signaling pathway; STAT3 directly binds to the FGFBP1 promoter and transactivates its expression; FGFBP1 secreted by PLA-treated cells promotes angiogenesis.","method":"ChIP for STAT3 on FGFBP1 promoter; mTOR inhibitor (rapamycin); STAT3 pathway assays; angiogenesis assay; OVA asthma mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding plus pharmacological pathway inhibition, single lab","pmids":["34341336"],"is_preprint":false},{"year":2023,"finding":"SGCE interacts with the Sp1 transcription factor and translocates to the nucleus, leading to transcriptional activation of FGF-BP1; secreted FGF-BP1 then activates FGF-FGFR signaling to promote breast cancer cell stemness.","method":"Co-immunoprecipitation of SGCE and Sp1; nuclear fractionation; SGCE overexpression/depletion; FGF-BP1 promoter reporter assay; stemness functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus nuclear translocation assay plus promoter reporter, single lab","pmids":["37838174"],"is_preprint":false},{"year":2023,"finding":"FGFBP1 acts as an extracellular ligand that rapidly elicits F-actin rearrangement and maintains cobblestone morphology in human keratinocytes; this function depends on HAI-1, as HAI-1 KO cells lose normal morphology and F-actin organization, which is restored by conditioned medium containing FGFBP1 or by recombinant FGFBP1 at ≥1 ng/ml; FGFBP1 was identified as the active factor in conditioned medium by tandem mass spectrometry.","method":"HAI-1 knockout in HaCaT cells; conditioned medium rescue; tandem mass spectrometry identification; recombinant FGFBP1 add-back; F-actin imaging","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification plus recombinant protein rescue with dose-response, single lab","pmids":["37076641"],"is_preprint":false},{"year":2023,"finding":"KLF5 transcription factor binds to the FGF-BP1 promoter and transcriptionally activates its expression in esophageal squamous cell carcinoma, contributing to tumor proliferation, migration, and invasion via FGF-BP1/SNAIL2 signaling.","method":"ChIP for KLF5 on FGFBP1 promoter; luciferase reporter assay; KLF5 overexpression/knockdown; cell proliferation and invasion assays","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter validation of direct promoter binding, single lab","pmids":["38087142"],"is_preprint":false},{"year":2025,"finding":"FGFBP1 overexpression in sheep adipocytes inhibits proliferation by causing G2/M cell cycle arrest and promotes adipocyte differentiation by upregulating PPARγ, Adiponectin, C/EBPα, and FABP4; knockdown has the opposite effects, establishing FGFBP1 as a regulator of adipogenesis.","method":"Overexpression and siRNA knockdown in ovine preadipocytes; cell cycle analysis; lipid droplet staining; RT-qPCR for adipogenic markers","journal":"Animals","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain- and loss-of-function with defined phenotype but no upstream mechanism or pathway placement, single lab","pmids":["40427333"],"is_preprint":false},{"year":2025,"finding":"During acute liver injury, FGF6 (induced by glucocorticoid signaling in skeletal muscle) regulates FGFBP1 expression through an ERK-ATF3 signaling pathway and perturbs FGFBP1 heparin-dependent release kinetics by disrupting FGFBP1 liquid-liquid phase separation (LLPS)-driven condensate dynamics at the plasma membrane; circulating FGFBP1 subsequently interacts with hepatic FGF5 via LLPS to regulate liver regeneration.","method":"RNA-seq; ATAC-seq; ChIP; luciferase assay; muscle-specific GR knockdown mice; Fgf6 knockout mice; FGF6 neutralizing antibody; LLPS/phase separation assay; ELISA for serum FGFBP1 in ALI patients","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo genetic and biochemical methods in single study, LLPS findings novel but not independently replicated","pmids":["40685360"],"is_preprint":false},{"year":2025,"finding":"FGFBP1 promotes TNBC cell proliferation, migration, and invasion by upregulating KLK10 expression, which activates AKT; knockdown of KLK10 or AKT inhibition impairs FGFBP1 overexpression-driven tumor cell phenotypes.","method":"FGFBP1 overexpression/knockdown in TNBC cell lines; KLK10 knockdown; AKT inhibitor; proliferation and invasion assays in vitro and in vivo (xenograft)","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis via double knockdown, single lab, no direct binding or upstream mechanism established","pmids":["40233428"],"is_preprint":false},{"year":2026,"finding":"Angiotensin II activates STAT3 in cardiomyocytes, which directly induces FGFBP1 transcription; FGFBP1 KO mice show significantly attenuated Ang II- and TAC-induced cardiac hypertrophy, dysfunction, and interstitial fibrosis; pharmacological STAT3 inhibition (S3I-201) reduces FGFBP1 expression and recapitulates the protective KO phenotype.","method":"FGFBP1 knockout mice; Ang II infusion and TAC models; RNA sequencing; STAT3 inhibitor (S3I-201); cardiac function and histology","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple cardiac phenotypes plus pharmacological pathway confirmation, single lab","pmids":["42013958"],"is_preprint":false}],"current_model":"FGFBP1 is a secreted extracellular chaperone that non-covalently binds FGF-1 and FGF-2 (and other FGFs) and releases them from heparan sulfate proteoglycans in the extracellular matrix via a heparin-binding site at residues 110–143, thereby mobilizing and bioactivating paracrine FGF signaling; its expression is transcriptionally regulated by multiple inputs including STAT3, C/EBP (ERK/p38-dependent), NF-κB (suppressed by vitamin D), Sp1 (via SGCE), KLF5, HMGA1, and CREB3L1 (miR-146a axis), and is subject to phosphorylation by PKA/CK1; in vivo, FGFBP1 controls vascular tone and blood pressure by sensitizing resistance vessels and renal arterioles to AngII through FGF receptor–AngII crosstalk via MKK4/p38/JNK MAPK, promotes blood-brain barrier maturation by concentrating Wnt ligands and supporting collagen IV deposition, maintains neuromuscular junction integrity in a TGF-β1-regulated manner, and drives pathological cardiac remodeling as a STAT3-dependent effector; additionally, FGFBP1 can act independently of FGFs to elicit F-actin rearrangement and maintain keratinocyte morphology in a HAI-1-dependent manner."},"narrative":{"mechanistic_narrative":"FGFBP1 is a secreted heparin-binding chaperone that mobilizes matrix-sequestered fibroblast growth factors to enable paracrine FGF signaling: purified recombinant protein directly binds FGF-2, releases it from the extracellular matrix, and stimulates endothelial and tumor cell proliferation and chemotaxis in an FGF-2-dependent manner [PMID:11304685], with heparin/heparan-sulfate binding mediated by a basic cluster at residues 110–143 [PMID:9784842]. By controlling FGF availability, FGFBP1 acts across vascular, neuromuscular, and tumor contexts. In the vasculature it sensitizes resistance vessels and renal afferent arterioles to angiotensin II constriction through FGF receptor kinase–dependent crosstalk integrated by MKK4/p38/JNK MAPK signaling, an effect lost in FGF2-null mice and restored by FGF2 plus FGFBP1 add-back, and sufficient to raise arterial blood pressure when transgenically expressed [PMID:29158353]; this same FGF2/FGFBP1 axis underlies brain vascular angiotensin II sensitization following acute kidney injury [PMID:33040621]. In brain endothelium FGFBP1 acts cell-autonomously to concentrate Wnt ligands at junctions, promoting Wnt/β-catenin-driven blood-brain barrier maturation and collagen IV basement-membrane deposition [PMID:32747434], and it is concentrated at neuromuscular junctions by muscle fibers, where its loss produces structural NMJ defects and accelerates degeneration in an ALS model [PMID:28053031]. FGFBP1 transcription is a convergence point for numerous inputs, being activated by STAT3 [PMID:34341336, PMID:42013958], C/EBP via ERK/p38 [PMID:11313920], KLF5 [PMID:38087142], and Sp1 downstream of SGCE [PMID:37838174], and repressed by vitamin D/VDR through NF-κB [PMID:23104116, PMID:24938357] and by CREB3L1, which is itself targeted by miR-146a [PMID:27121396]; in cancers it drives proliferation, migration, and invasion via downstream FGF-FGFR, AKT, and SNAIL2/KLK10 signaling [PMID:32195034, PMID:34117747, PMID:38087142]. Beyond FGF mobilization, FGFBP1 acts as an extracellular ligand that drives F-actin rearrangement and maintains keratinocyte cobblestone morphology in a HAI-1-dependent manner [PMID:37076641].","teleology":[{"year":1998,"claim":"Localizing the heparin-binding determinant established how FGFBP1 physically docks onto the heparan-sulfate matrix where FGFs are sequestered.","evidence":"Protease peptide mapping and heparin-Sepharose affinity isolation of binding fragments","pmids":["9784842"],"confidence":"Medium","gaps":["No mutagenesis validation of the 110–143 cluster","Does not address FGF-binding site location","Single lab"]},{"year":2001,"claim":"Reconstitution with purified protein answered whether FGFBP1 directly binds and mobilizes FGF-2, establishing it as a paracrine FGF chaperone rather than an autonomous growth factor.","evidence":"In vitro binding, ECM release, proliferation/chemotaxis assays with antibody neutralization","pmids":["11304685"],"confidence":"High","gaps":["Stoichiometry and structure of the FGFBP1–FGF complex not resolved","Receptor-level consequences not directly measured"]},{"year":2001,"claim":"Mapping the serum-responsive promoter elements defined the kinase cascades and transcription factors that drive FGFBP1 expression, distinguishing it from EGF-driven induction.","evidence":"Promoter deletion/mutagenesis, kinase inhibitors, run-on assay in SCC cells","pmids":["11313920"],"confidence":"Medium","gaps":["Direct C/EBP binding not shown by ChIP","Single cell-type context"]},{"year":2005,"claim":"Identification of FGFBP1 as a phosphoacceptor for PKA, CK1, and CK2 raised the possibility that phosphorylation tunes its FGF/lactoferrin-binding behavior.","evidence":"In vitro kinase assays and binding affinity measurements on milk-purified bovine ortholog","pmids":["16412577","17560725"],"confidence":"Medium","gaps":["Phosphoregulation not demonstrated in vivo in human FGFBP1","Physiological role of milk-derived fragments unclear"]},{"year":2010,"claim":"Zebrafish knockdown tested whether FGFBP1 is developmentally essential and whether all its functions route through FGF2, revealing an FGF2-independent survival requirement.","evidence":"Morpholino knockdown with cell-death assays compared to fgf2 morphants","pmids":["20396962"],"confidence":"Medium","gaps":["Morpholino off-target effects not excluded by genetic mutant","Molecular basis of FGF2-independent survival role undefined"]},{"year":2014,"claim":"Vitamin D/VDR/NF-κB suppression of FGFBP1 was linked functionally to reduced FGF-2 secretion, confirming FGFBP1 as required for FGF-2 release in living cells.","evidence":"Luciferase reporter, VDR siRNA, immunofluorescence, and FGF-2 ELISA in OSCC cells","pmids":["23104116","24938357"],"confidence":"Medium","gaps":["Direct NF-κB occupancy of FGFBP1 promoter not shown","Single tumor-cell context"]},{"year":2016,"claim":"The miR-146a/CREB3L1 axis was defined as a repressive layer controlling FGFBP1-dependent FGF2 secretion and angiogenesis.","evidence":"FGFBP1 promoter luciferase, ChIP, CREB3L1 manipulation, and FGF2 ELISA in HUVECs","pmids":["27121396"],"confidence":"Medium","gaps":["In vivo relevance of this axis not established","Single endothelial model"]},{"year":2017,"claim":"Genetic knockout established a physiological, FGF-mobilizing role for FGFBP1 in maintaining neuromuscular junction integrity, and identified TGF-β1 as a suppressing input under muscle stress.","evidence":"FGFBP1 KO and SOD1G93A ALS mice, NMJ structural and survival analysis, TGF-β1 treatment","pmids":["28053031"],"confidence":"High","gaps":["Which FGF(s) mediate the NMJ effect not pinned down","Mechanism of FGFBP1 concentration at the synapse unresolved"]},{"year":2017,"claim":"An inducible transgenic and FGF2-null rescue strategy demonstrated that FGFBP1 controls blood pressure by sensitizing vessels to angiotensin II through FGF receptor–MAPK crosstalk, defining a cardiovascular function.","evidence":"Inducible BP1 transgenic and FGF2−/− mice, telemetry, isolated vessel pharmacology, FGFR/ROS inhibitors","pmids":["29158353"],"confidence":"High","gaps":["Molecular point of FGFR–AngII receptor convergence not structurally defined","Cell type driving vessel sensitization not isolated"]},{"year":2020,"claim":"Conditional endothelial knockout revealed a distinct FGF-independent-looking role: concentrating Wnt ligands to drive blood-brain barrier maturation and basement-membrane assembly.","evidence":"Endothelial-specific Fgfbp1 KO mice, tracer leakage, Plvap/collagen IV staining, in vitro Wnt localization","pmids":["32747434"],"confidence":"High","gaps":["Direct FGFBP1–Wnt binding not biochemically demonstrated","How a heparin-binding chaperone localizes Wnt versus FGF unresolved"]},{"year":2020,"claim":"Knockout and protein add-back extended the AngII-sensitization mechanism to a kidney–brain vascular axis, showing FGFBP1 mediates inter-organ vascular crosstalk after acute kidney injury.","evidence":"Renal ischemia-reperfusion model, Fgfbp1 KO mice, vessel constriction with FGF2/FGFBP1 add-back, FGFR inhibitor","pmids":["33040621"],"confidence":"High","gaps":["Signal carrying FGFBP1 induction from kidney to brain not defined","Human relevance inferential"]},{"year":2019,"claim":"Cancer studies placed FGFBP1 within oncogenic signaling, downstream of FBW7/c-Myc and HSD11B2, and upstream of AKT/FGFR/SNAIL2/KLK10 effectors driving proliferation and metastasis.","evidence":"Epistatic knockdown/rescue, co-culture, ChIP/luciferase, and xenograft assays across pancreatic, colorectal, esophageal, and breast cancer models","pmids":["31911852","32195034","34117747","37838174","38087142","40233428"],"confidence":"Medium","gaps":["Direct physical interactions among most named effectors not demonstrated","Cancer-type-specific wiring not unified mechanistically"]},{"year":2021,"claim":"ChIP-level evidence defined STAT3 as a direct activator of FGFBP1, downstream of mTORC1, linking inflammatory/airway stimuli to FGFBP1-driven angiogenesis.","evidence":"STAT3 ChIP on FGFBP1 promoter, rapamycin inhibition, angiogenesis assay, OVA asthma model","pmids":["34341336"],"confidence":"Medium","gaps":["Single airway context","Downstream FGF target of secreted FGFBP1 not specified"]},{"year":2023,"claim":"Mass-spectrometry-guided rescue revealed an FGF-independent activity of FGFBP1 as an extracellular ligand maintaining keratinocyte cytoskeleton and morphology via HAI-1.","evidence":"HAI-1 KO HaCaT cells, conditioned-medium and recombinant FGFBP1 rescue, tandem MS, F-actin imaging","pmids":["37076641"],"confidence":"Medium","gaps":["Receptor mediating the HAI-1-dependent response not identified","Direct FGFBP1–HAI-1 binding not shown"]},{"year":2025,"claim":"An ERK-ATF3 and liquid-liquid phase separation framework was proposed for how FGF6 tunes FGFBP1 release kinetics and how circulating FGFBP1 engages hepatic FGF5 during liver regeneration.","evidence":"Multi-omics, muscle-GR and Fgf6 knockout mice, LLPS/condensate assays, serum FGFBP1 ELISA in patients","pmids":["40685360"],"confidence":"Medium","gaps":["LLPS-driven release not independently replicated","Structural basis of condensate formation undefined"]},{"year":2026,"claim":"Knockout plus pharmacological inhibition established FGFBP1 as a STAT3-dependent effector of angiotensin II-driven pathological cardiac remodeling.","evidence":"FGFBP1 KO mice in AngII/TAC models, RNA-seq, STAT3 inhibitor S3I-201, cardiac histology","pmids":["42013958"],"confidence":"Medium","gaps":["FGF effector mediating cardiac hypertrophy not identified","Cell-type-specific source of FGFBP1 in heart not resolved"]},{"year":null,"claim":"It remains unresolved how a single heparin-binding chaperone selectively mobilizes distinct ligand classes (FGF-1/2, FGF22, FGF5, Wnt) in different tissues and which receptor mediates its FGF-independent cytoskeletal activity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of FGFBP1 in complex with any ligand","Mechanism distinguishing FGF- versus Wnt-mobilizing modes unknown","Receptor for FGF-independent signaling unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,8,13]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,8,10]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11,14]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,13]}],"complexes":[],"partners":["FGF2","FGF22","FGF5","HAI-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14512","full_name":"Fibroblast growth factor-binding protein 1","aliases":["17 kDa heparin-binding growth factor-binding protein","17 kDa HBGF-binding protein","HBp17"],"length_aa":234,"mass_kda":26.3,"function":"Acts as a carrier protein that release fibroblast-binding factors (FGFs) from the extracellular matrix (EM) storage and thus enhance the mitogenic activity of FGFs. Enhances FGF2 signaling during tissue repair, angiogenesis and in tumor growth","subcellular_location":"Secreted, extracellular space; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14512/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FGFBP1","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/FGFBP1","total_profiled":1310},"omim":[{"mim_id":"620879","title":"FIBROBLAST GROWTH FACTOR-BINDING PROTEIN 3; FGFBP3","url":"https://www.omim.org/entry/620879"},{"mim_id":"607737","title":"FIBROBLAST GROWTH FACTOR-BINDING PROTEIN 1; FGFBP1","url":"https://www.omim.org/entry/607737"},{"mim_id":"607713","title":"FIBROBLAST GROWTH FACTOR-BINDING PROTEIN 2; FGFBP2","url":"https://www.omim.org/entry/607713"},{"mim_id":"142461","title":"HEPARAN SULFATE PROTEOGLYCAN OF BASEMENT MEMBRANE; HSPG2","url":"https://www.omim.org/entry/142461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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cell proliferation and chemotaxis assays; antibody neutralization; immunodetection of high-molecular-weight FGF-BP complexes in xenografts\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified recombinant protein, antibody neutralization, and multiple functional readouts in a single study\",\n      \"pmids\": [\"11304685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The heparin-binding site of FGFBP1 (HBp17) was mapped to residues 110–143 using protease digestion (V8 and chymotrypsin) followed by heparin-Sepharose isolation of binding fragments; a basic amino acid cluster in this region mediates binding to heparin/heparan sulfate proteoglycan.\",\n      \"method\": \"Protease peptide mapping; heparin-Sepharose affinity chromatography of peptide fragments\",\n      \"journal\": \"Biochemistry and molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct biochemical mapping with two proteases, single lab, no mutagenesis validation\",\n      \"pmids\": [\"9784842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Serum induction of FGF-BP mRNA in squamous cell carcinoma cells is dependent on PKC, ERK kinase (MEK), and p38 MAP kinase activation, and the C/EBP promoter element is the main element required for this serum response; the mechanism differs from EGF-mediated induction (which uses AP-1 and E-box sites).\",\n      \"method\": \"Promoter analysis; kinase inhibitors; transcription run-on assay; site-directed mutagenesis of promoter elements\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion analysis combined with pharmacological pathway inhibition, single lab, two orthogonal methods\",\n      \"pmids\": [\"11313920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HBp17 (FGFBP1) exhibits a biphasic dose-dependent effect on DNA synthesis: low concentrations (8 ng/ml) maximally stimulate DNA synthesis while high concentrations (~500 ng/ml) cause half-maximal inhibition, and this inhibition is reversed by addition of aFGF or bFGF but not EGF.\",\n      \"method\": \"DNA synthesis assay in 3T3 cells and HUVECs at varying HBp17 concentrations; FGF rescue experiment\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional assay with defined dose-response and FGF rescue, single lab, single method\",\n      \"pmids\": [\"11407864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Bovine FGF-BP (FGFBP1 ortholog, p37) purified from milk has higher binding affinity for bFGF than lactoferrin, serves as a phosphate acceptor for PKA, CK1, and CK2, and full phosphorylation by PKA abolishes its binding to lactoferrin in vitro; sulfatide-induced conformational changes enable CK1-mediated phosphorylation and also reduce lactoferrin binding.\",\n      \"method\": \"Heparin-HPLC purification; in vitro kinase assays (PKA, CK1, CK2); binding affinity assay; N-terminal sequencing\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical reconstitution with purified protein, multiple kinases tested, single lab\",\n      \"pmids\": [\"16412577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"N-terminal fragment p5 (residues 24–51) cleaved from FGF-BP in bovine milk is phosphorylated by PKA and CK1δ; CK1δ phosphorylation requires sulfated lipids (sulfatide or cholesterol-3-sulfate); a novel CK1δ phosphorylation site (RNRRGS) and SCS-binding site (RNRR) were identified; p5 (but not phosphorylated p5) directly binds aFGF.\",\n      \"method\": \"Gel filtration purification; in vitro kinase assays; immunoprecipitation; synthetic peptide analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical reconstitution with purified fragment and synthetic peptides, single lab\",\n      \"pmids\": [\"17560725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Morpholino-mediated knockdown of Fgfbp1 in zebrafish causes massive cell death prominently in brain and neural tube, indicating that Fgfbp1 is essential for cellular survival during embryogenesis; this function appears to be at least partly FGF2-independent, as fgf2 morphants show a more severe and earlier phenotype.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos; cell death assay; comparison with fgf2 morphants\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with defined cellular phenotype and FGF2-independence inference, single lab\",\n      \"pmids\": [\"20396962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"1α,25(OH)2D3 downregulates HBp17/FGFBP1 mRNA and protein in oral squamous cell carcinoma cells via the NF-κB pathway (upregulating IκBα), and this effect requires vitamin D receptor (VDR); luciferase assay identified the responsive promoter region between −217 and +61.\",\n      \"method\": \"RT-PCR; Western blotting; luciferase reporter assay; VDR siRNA knockdown\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay plus siRNA confirmation plus mRNA/protein quantification, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23104116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"1α,25(OH)2D3 suppresses HBp17/FGFBP1 expression in both nucleus and cytosol of OSCC cells via NF-κB/VDR pathway, and this suppression results in reduced FGF-2 release into culture medium, establishing FGFBP1 as a chaperone required for FGF-2 secretion.\",\n      \"method\": \"Immunofluorescence; ELISA for FGF-2 in conditioned medium; pharmacological treatment\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (immunofluorescence localization + ELISA functional readout), single lab\",\n      \"pmids\": [\"24938357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREB3L1 suppresses FGFBP1 expression by binding to two CRE-like sites at approximately −1780 and −868 bp in the FGFBP1 promoter; miR-146a targets CREB3L1, thereby de-repressing FGFBP1 expression and increasing FGF2 secretion to promote angiogenesis in HUVECs.\",\n      \"method\": \"Luciferase reporter assay with FGFBP1 promoter; ChIP; CREB3L1 overexpression; FGF2 ELISA; lentiviral miR-146a overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter + ChIP + functional ELISA readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27121396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Muscle fibers secrete and concentrate FGFBP1 at neuromuscular junctions (NMJs); FGFBP1 expression decreases before NMJ degeneration during aging and in SOD1G93A ALS mice; genetic deletion of FGFBP1 causes NMJ structural abnormalities and accelerates NMJ degeneration and death in SOD1G93A mice; TGF-β1 accumulation in stressed muscles inhibits FGFBP1 expression.\",\n      \"method\": \"FGFBP1 knockout mice; SOD1G93A mouse model; NMJ structural analysis; survival assay; TGF-β1 treatment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific structural and survival phenotypes, disease model validation, TGF-β1 mechanism identified, multiple orthogonal experiments\",\n      \"pmids\": [\"28053031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Inducible transgenic expression of FGFBP1 (BP1) in adult mice causes a sustained >30 mmHg rise in mean arterial blood pressure; this hypertensive effect is prevented by the AngII receptor antagonist candesartan or by the ROS inhibitor tempol; BP1 expression sensitizes peripheral resistance vessels and renal afferent arterioles to AngII constriction by ~20-fold via FGF receptor kinase-dependent signaling; AngII-mediated constriction is abolished in FGF2−/− mice but restored by FGF2 + BP1 add-back; MAPK signaling via MKK4, p38, and JNK integrates FGF receptor and AngII pathway crosstalk.\",\n      \"method\": \"Inducible transgenic mouse model; blood pressure telemetry; pharmacological inhibition (candesartan, tempol, FGFR kinase inhibitor); isolated vessel constriction assay; FGF2−/− mice with protein add-back; proteomics and gene expression analysis of kidney\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible transgenic model plus knockout rescue plus isolated vessel pharmacology plus multiple pathway validations in one rigorous study\",\n      \"pmids\": [\"29158353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FGFBP1 is regulated by the FBW7/c-Myc axis in pancreatic cancer: FBW7 reduces FGFBP1 expression in a c-Myc-dependent manner; FGFBP1 silencing inhibits pancreatic cancer cell proliferation and metastasis, and FBW7 silencing partially reverses the effects of FGFBP1 silencing.\",\n      \"method\": \"siRNA knockdown; overexpression; co-expression correlation in patient tissue; epistasis rescue experiments in cell lines\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis via double knockdown/rescue experiments, single lab\",\n      \"pmids\": [\"31911852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial genetic ablation of Fgfbp1 in mice causes transient hypervascularization, delays blood-brain barrier maturation (increased Plvap, increased tracer leakage) due to reduced Wnt/β-catenin activity, and reduces collagen IV deposition in the vascular basement membrane leading to defective pericyte interactions; Fgfbp1 acts cell-autonomously in brain endothelial cells to concentrate Wnt ligands near cell junctions.\",\n      \"method\": \"Endothelial-specific Fgfbp1 knockout mice; tracer leakage assay; immunostaining for Plvap and collagen IV; in vitro barrier assay with Wnt ligand localization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple orthogonal functional readouts (permeability, molecular markers, ECM composition, cell-cell interactions) in vivo and in vitro\",\n      \"pmids\": [\"32747434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGFBP1 mediates AKI-induced brain vascular sensitization to AngII: after bilateral renal ischemia-reperfusion injury, FGF2 and FGFBP1 are upregulated in serum and kidney; exogenous FGF2 + FGFBP1 proteins applied to healthy brain vessels mimic AKI-induced AngII sensitization; Fgfbp1−/− AKI mice fail to develop brain vascular AngII sensitization; FGFR kinase inhibition (BGJ398) reverses sensitization.\",\n      \"method\": \"Bilateral renal ischemia-reperfusion mouse model; Fgfbp1 knockout mice; isolated vessel constriction assay; protein add-back; FGFR inhibitor treatment\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout model plus protein add-back plus pharmacological inhibition across multiple orthogonal experiments, replicated mechanistic finding consistent with prior BP study\",\n      \"pmids\": [\"33040621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSD11B2 promotes colorectal cancer cell migration and invasion by upregulating FGFBP1 expression, which subsequently increases AKT phosphorylation; knockdown of either FGFBP1 or AKT impairs the migration/invasion promoted by HSD11B2 overexpression, placing FGFBP1 downstream of HSD11B2 in the HSD11B2-FGFBP1-AKT pathway.\",\n      \"method\": \"mRNA transcriptome array; overexpression and knockdown in CRC cell lines; in vitro migration/invasion assay; in vivo metastasis model; AKT phosphorylation Western blot\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via double knockdown and rescue, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"32195034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In pancreatic cancer, FGFBP1 expressed in cancer-associated fibroblasts (CAFs) promotes FGF22 release; FGF22 activates FGFR2 on pancreatic cancer cells to facilitate their invasion and metastasis; silencing FGFR2 in cancer cells blocks FGF22-driven invasion even with FGF22 treatment.\",\n      \"method\": \"Co-culture of CAFs with pancreatic cancer cells; FGFBP1 knockdown; ELISA for FGF22 in conditioned medium; siRNA knockdown of FGF22 and FGFR2; invasion assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ELISA plus co-culture functional assay plus receptor knockdown epistasis, single lab\",\n      \"pmids\": [\"34117747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Poly-L-arginine (mimic of eosinophil major basic protein) induces FGFBP1 expression in airway epithelial cells via activation of the mTORC1-STAT3 signaling pathway; STAT3 directly binds to the FGFBP1 promoter and transactivates its expression; FGFBP1 secreted by PLA-treated cells promotes angiogenesis.\",\n      \"method\": \"ChIP for STAT3 on FGFBP1 promoter; mTOR inhibitor (rapamycin); STAT3 pathway assays; angiogenesis assay; OVA asthma mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding plus pharmacological pathway inhibition, single lab\",\n      \"pmids\": [\"34341336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SGCE interacts with the Sp1 transcription factor and translocates to the nucleus, leading to transcriptional activation of FGF-BP1; secreted FGF-BP1 then activates FGF-FGFR signaling to promote breast cancer cell stemness.\",\n      \"method\": \"Co-immunoprecipitation of SGCE and Sp1; nuclear fractionation; SGCE overexpression/depletion; FGF-BP1 promoter reporter assay; stemness functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus nuclear translocation assay plus promoter reporter, single lab\",\n      \"pmids\": [\"37838174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FGFBP1 acts as an extracellular ligand that rapidly elicits F-actin rearrangement and maintains cobblestone morphology in human keratinocytes; this function depends on HAI-1, as HAI-1 KO cells lose normal morphology and F-actin organization, which is restored by conditioned medium containing FGFBP1 or by recombinant FGFBP1 at ≥1 ng/ml; FGFBP1 was identified as the active factor in conditioned medium by tandem mass spectrometry.\",\n      \"method\": \"HAI-1 knockout in HaCaT cells; conditioned medium rescue; tandem mass spectrometry identification; recombinant FGFBP1 add-back; F-actin imaging\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification plus recombinant protein rescue with dose-response, single lab\",\n      \"pmids\": [\"37076641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLF5 transcription factor binds to the FGF-BP1 promoter and transcriptionally activates its expression in esophageal squamous cell carcinoma, contributing to tumor proliferation, migration, and invasion via FGF-BP1/SNAIL2 signaling.\",\n      \"method\": \"ChIP for KLF5 on FGFBP1 promoter; luciferase reporter assay; KLF5 overexpression/knockdown; cell proliferation and invasion assays\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter validation of direct promoter binding, single lab\",\n      \"pmids\": [\"38087142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGFBP1 overexpression in sheep adipocytes inhibits proliferation by causing G2/M cell cycle arrest and promotes adipocyte differentiation by upregulating PPARγ, Adiponectin, C/EBPα, and FABP4; knockdown has the opposite effects, establishing FGFBP1 as a regulator of adipogenesis.\",\n      \"method\": \"Overexpression and siRNA knockdown in ovine preadipocytes; cell cycle analysis; lipid droplet staining; RT-qPCR for adipogenic markers\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain- and loss-of-function with defined phenotype but no upstream mechanism or pathway placement, single lab\",\n      \"pmids\": [\"40427333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During acute liver injury, FGF6 (induced by glucocorticoid signaling in skeletal muscle) regulates FGFBP1 expression through an ERK-ATF3 signaling pathway and perturbs FGFBP1 heparin-dependent release kinetics by disrupting FGFBP1 liquid-liquid phase separation (LLPS)-driven condensate dynamics at the plasma membrane; circulating FGFBP1 subsequently interacts with hepatic FGF5 via LLPS to regulate liver regeneration.\",\n      \"method\": \"RNA-seq; ATAC-seq; ChIP; luciferase assay; muscle-specific GR knockdown mice; Fgf6 knockout mice; FGF6 neutralizing antibody; LLPS/phase separation assay; ELISA for serum FGFBP1 in ALI patients\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo genetic and biochemical methods in single study, LLPS findings novel but not independently replicated\",\n      \"pmids\": [\"40685360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGFBP1 promotes TNBC cell proliferation, migration, and invasion by upregulating KLK10 expression, which activates AKT; knockdown of KLK10 or AKT inhibition impairs FGFBP1 overexpression-driven tumor cell phenotypes.\",\n      \"method\": \"FGFBP1 overexpression/knockdown in TNBC cell lines; KLK10 knockdown; AKT inhibitor; proliferation and invasion assays in vitro and in vivo (xenograft)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis via double knockdown, single lab, no direct binding or upstream mechanism established\",\n      \"pmids\": [\"40233428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Angiotensin II activates STAT3 in cardiomyocytes, which directly induces FGFBP1 transcription; FGFBP1 KO mice show significantly attenuated Ang II- and TAC-induced cardiac hypertrophy, dysfunction, and interstitial fibrosis; pharmacological STAT3 inhibition (S3I-201) reduces FGFBP1 expression and recapitulates the protective KO phenotype.\",\n      \"method\": \"FGFBP1 knockout mice; Ang II infusion and TAC models; RNA sequencing; STAT3 inhibitor (S3I-201); cardiac function and histology\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple cardiac phenotypes plus pharmacological pathway confirmation, single lab\",\n      \"pmids\": [\"42013958\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGFBP1 is a secreted extracellular chaperone that non-covalently binds FGF-1 and FGF-2 (and other FGFs) and releases them from heparan sulfate proteoglycans in the extracellular matrix via a heparin-binding site at residues 110–143, thereby mobilizing and bioactivating paracrine FGF signaling; its expression is transcriptionally regulated by multiple inputs including STAT3, C/EBP (ERK/p38-dependent), NF-κB (suppressed by vitamin D), Sp1 (via SGCE), KLF5, HMGA1, and CREB3L1 (miR-146a axis), and is subject to phosphorylation by PKA/CK1; in vivo, FGFBP1 controls vascular tone and blood pressure by sensitizing resistance vessels and renal arterioles to AngII through FGF receptor–AngII crosstalk via MKK4/p38/JNK MAPK, promotes blood-brain barrier maturation by concentrating Wnt ligands and supporting collagen IV deposition, maintains neuromuscular junction integrity in a TGF-β1-regulated manner, and drives pathological cardiac remodeling as a STAT3-dependent effector; additionally, FGFBP1 can act independently of FGFs to elicit F-actin rearrangement and maintain keratinocyte morphology in a HAI-1-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGFBP1 is a secreted heparin-binding chaperone that mobilizes matrix-sequestered fibroblast growth factors to enable paracrine FGF signaling: purified recombinant protein directly binds FGF-2, releases it from the extracellular matrix, and stimulates endothelial and tumor cell proliferation and chemotaxis in an FGF-2-dependent manner [#0], with heparin/heparan-sulfate binding mediated by a basic cluster at residues 110–143 [#1]. By controlling FGF availability, FGFBP1 acts across vascular, neuromuscular, and tumor contexts. In the vasculature it sensitizes resistance vessels and renal afferent arterioles to angiotensin II constriction through FGF receptor kinase–dependent crosstalk integrated by MKK4/p38/JNK MAPK signaling, an effect lost in FGF2-null mice and restored by FGF2 plus FGFBP1 add-back, and sufficient to raise arterial blood pressure when transgenically expressed [#11]; this same FGF2/FGFBP1 axis underlies brain vascular angiotensin II sensitization following acute kidney injury [#14]. In brain endothelium FGFBP1 acts cell-autonomously to concentrate Wnt ligands at junctions, promoting Wnt/β-catenin-driven blood-brain barrier maturation and collagen IV basement-membrane deposition [#13], and it is concentrated at neuromuscular junctions by muscle fibers, where its loss produces structural NMJ defects and accelerates degeneration in an ALS model [#10]. FGFBP1 transcription is a convergence point for numerous inputs, being activated by STAT3 [#17, #24], C/EBP via ERK/p38 [#2], KLF5 [#20], and Sp1 downstream of SGCE [#18], and repressed by vitamin D/VDR through NF-κB [#7, #8] and by CREB3L1, which is itself targeted by miR-146a [#9]; in cancers it drives proliferation, migration, and invasion via downstream FGF-FGFR, AKT, and SNAIL2/KLK10 signaling [#15, #16, #20]. Beyond FGF mobilization, FGFBP1 acts as an extracellular ligand that drives F-actin rearrangement and maintains keratinocyte cobblestone morphology in a HAI-1-dependent manner [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Localizing the heparin-binding determinant established how FGFBP1 physically docks onto the heparan-sulfate matrix where FGFs are sequestered.\",\n      \"evidence\": \"Protease peptide mapping and heparin-Sepharose affinity isolation of binding fragments\",\n      \"pmids\": [\"9784842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of the 110–143 cluster\", \"Does not address FGF-binding site location\", \"Single lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstitution with purified protein answered whether FGFBP1 directly binds and mobilizes FGF-2, establishing it as a paracrine FGF chaperone rather than an autonomous growth factor.\",\n      \"evidence\": \"In vitro binding, ECM release, proliferation/chemotaxis assays with antibody neutralization\",\n      \"pmids\": [\"11304685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the FGFBP1–FGF complex not resolved\", \"Receptor-level consequences not directly measured\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapping the serum-responsive promoter elements defined the kinase cascades and transcription factors that drive FGFBP1 expression, distinguishing it from EGF-driven induction.\",\n      \"evidence\": \"Promoter deletion/mutagenesis, kinase inhibitors, run-on assay in SCC cells\",\n      \"pmids\": [\"11313920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct C/EBP binding not shown by ChIP\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of FGFBP1 as a phosphoacceptor for PKA, CK1, and CK2 raised the possibility that phosphorylation tunes its FGF/lactoferrin-binding behavior.\",\n      \"evidence\": \"In vitro kinase assays and binding affinity measurements on milk-purified bovine ortholog\",\n      \"pmids\": [\"16412577\", \"17560725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoregulation not demonstrated in vivo in human FGFBP1\", \"Physiological role of milk-derived fragments unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Zebrafish knockdown tested whether FGFBP1 is developmentally essential and whether all its functions route through FGF2, revealing an FGF2-independent survival requirement.\",\n      \"evidence\": \"Morpholino knockdown with cell-death assays compared to fgf2 morphants\",\n      \"pmids\": [\"20396962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not excluded by genetic mutant\", \"Molecular basis of FGF2-independent survival role undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Vitamin D/VDR/NF-κB suppression of FGFBP1 was linked functionally to reduced FGF-2 secretion, confirming FGFBP1 as required for FGF-2 release in living cells.\",\n      \"evidence\": \"Luciferase reporter, VDR siRNA, immunofluorescence, and FGF-2 ELISA in OSCC cells\",\n      \"pmids\": [\"23104116\", \"24938357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NF-κB occupancy of FGFBP1 promoter not shown\", \"Single tumor-cell context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The miR-146a/CREB3L1 axis was defined as a repressive layer controlling FGFBP1-dependent FGF2 secretion and angiogenesis.\",\n      \"evidence\": \"FGFBP1 promoter luciferase, ChIP, CREB3L1 manipulation, and FGF2 ELISA in HUVECs\",\n      \"pmids\": [\"27121396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of this axis not established\", \"Single endothelial model\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic knockout established a physiological, FGF-mobilizing role for FGFBP1 in maintaining neuromuscular junction integrity, and identified TGF-β1 as a suppressing input under muscle stress.\",\n      \"evidence\": \"FGFBP1 KO and SOD1G93A ALS mice, NMJ structural and survival analysis, TGF-β1 treatment\",\n      \"pmids\": [\"28053031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which FGF(s) mediate the NMJ effect not pinned down\", \"Mechanism of FGFBP1 concentration at the synapse unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"An inducible transgenic and FGF2-null rescue strategy demonstrated that FGFBP1 controls blood pressure by sensitizing vessels to angiotensin II through FGF receptor–MAPK crosstalk, defining a cardiovascular function.\",\n      \"evidence\": \"Inducible BP1 transgenic and FGF2−/− mice, telemetry, isolated vessel pharmacology, FGFR/ROS inhibitors\",\n      \"pmids\": [\"29158353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular point of FGFR–AngII receptor convergence not structurally defined\", \"Cell type driving vessel sensitization not isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional endothelial knockout revealed a distinct FGF-independent-looking role: concentrating Wnt ligands to drive blood-brain barrier maturation and basement-membrane assembly.\",\n      \"evidence\": \"Endothelial-specific Fgfbp1 KO mice, tracer leakage, Plvap/collagen IV staining, in vitro Wnt localization\",\n      \"pmids\": [\"32747434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FGFBP1–Wnt binding not biochemically demonstrated\", \"How a heparin-binding chaperone localizes Wnt versus FGF unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Knockout and protein add-back extended the AngII-sensitization mechanism to a kidney–brain vascular axis, showing FGFBP1 mediates inter-organ vascular crosstalk after acute kidney injury.\",\n      \"evidence\": \"Renal ischemia-reperfusion model, Fgfbp1 KO mice, vessel constriction with FGF2/FGFBP1 add-back, FGFR inhibitor\",\n      \"pmids\": [\"33040621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal carrying FGFBP1 induction from kidney to brain not defined\", \"Human relevance inferential\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cancer studies placed FGFBP1 within oncogenic signaling, downstream of FBW7/c-Myc and HSD11B2, and upstream of AKT/FGFR/SNAIL2/KLK10 effectors driving proliferation and metastasis.\",\n      \"evidence\": \"Epistatic knockdown/rescue, co-culture, ChIP/luciferase, and xenograft assays across pancreatic, colorectal, esophageal, and breast cancer models\",\n      \"pmids\": [\"31911852\", \"32195034\", \"34117747\", \"37838174\", \"38087142\", \"40233428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interactions among most named effectors not demonstrated\", \"Cancer-type-specific wiring not unified mechanistically\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ChIP-level evidence defined STAT3 as a direct activator of FGFBP1, downstream of mTORC1, linking inflammatory/airway stimuli to FGFBP1-driven angiogenesis.\",\n      \"evidence\": \"STAT3 ChIP on FGFBP1 promoter, rapamycin inhibition, angiogenesis assay, OVA asthma model\",\n      \"pmids\": [\"34341336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single airway context\", \"Downstream FGF target of secreted FGFBP1 not specified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mass-spectrometry-guided rescue revealed an FGF-independent activity of FGFBP1 as an extracellular ligand maintaining keratinocyte cytoskeleton and morphology via HAI-1.\",\n      \"evidence\": \"HAI-1 KO HaCaT cells, conditioned-medium and recombinant FGFBP1 rescue, tandem MS, F-actin imaging\",\n      \"pmids\": [\"37076641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the HAI-1-dependent response not identified\", \"Direct FGFBP1–HAI-1 binding not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An ERK-ATF3 and liquid-liquid phase separation framework was proposed for how FGF6 tunes FGFBP1 release kinetics and how circulating FGFBP1 engages hepatic FGF5 during liver regeneration.\",\n      \"evidence\": \"Multi-omics, muscle-GR and Fgf6 knockout mice, LLPS/condensate assays, serum FGFBP1 ELISA in patients\",\n      \"pmids\": [\"40685360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LLPS-driven release not independently replicated\", \"Structural basis of condensate formation undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Knockout plus pharmacological inhibition established FGFBP1 as a STAT3-dependent effector of angiotensin II-driven pathological cardiac remodeling.\",\n      \"evidence\": \"FGFBP1 KO mice in AngII/TAC models, RNA-seq, STAT3 inhibitor S3I-201, cardiac histology\",\n      \"pmids\": [\"42013958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FGF effector mediating cardiac hypertrophy not identified\", \"Cell-type-specific source of FGFBP1 in heart not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single heparin-binding chaperone selectively mobilizes distinct ligand classes (FGF-1/2, FGF22, FGF5, Wnt) in different tissues and which receptor mediates its FGF-independent cytoskeletal activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of FGFBP1 in complex with any ligand\", \"Mechanism distinguishing FGF- versus Wnt-mobilizing modes unknown\", \"Receptor for FGF-independent signaling unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 8, 13]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 8, 10]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11, 14]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGF2\", \"FGF22\", \"FGF5\", \"HAI-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}