{"gene":"FGF7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1991,"finding":"KGF (FGF7) signals through a specific high-affinity tyrosine kinase receptor (KGFR/FGFR2 IIIb) that is distinct from the basic FGF receptor; expression cloning in NIH/3T3 fibroblasts demonstrated acquisition of specific high-affinity KGF binding sites and transformation via an autocrine loop.","method":"Expression cDNA cloning, ligand binding competition assays, focus formation/transformation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct receptor cloning with functional validation (binding, transformation), foundational study replicated across many subsequent papers","pmids":["1846048"],"is_preprint":false},{"year":1994,"finding":"KGF receptor signaling in basal keratinocytes is required for normal epidermal morphogenesis and reepithelialization of wounds; dominant-negative KGFR transgene in mice caused epidermal atrophy, hair follicle abnormalities, dermal hyperthickening, and substantially delayed wound reepithelialization with reduced keratinocyte proliferation at wound edges.","method":"Dominant-negative transgene expression in mouse basal keratinocytes, skin histology, wound healing assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function (dominant-negative transgene) with defined cellular phenotype (epidermal atrophy, impaired wound healing), widely replicated","pmids":["7973639"],"is_preprint":false},{"year":1994,"finding":"Cell-associated heparan sulfates differentially modulate KGF binding to KGFR: heparin inhibits KGF binding to KGFR whereas it enhances aFGF binding to the same receptor; removal of cell-surface heparan sulfates (chlorate treatment or heparinase) enhances KGF high-affinity binding ~2-fold. KGF also interacts with an unidentified low-affinity binding site unaffected by heparan sulfate removal.","method":"Radioligand binding assays, sodium chlorate treatment to block proteoglycan sulfation, heparinase/heparitinase digestion, competition binding in L6E9 cells expressing KGFR and Balb/MK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in defined cell lines with multiple orthogonal biochemical methods and mechanistic controls","pmids":["7528211"],"is_preprint":false},{"year":1996,"finding":"The KGF/FGF7 promoter is directly regulated by androgens; androgen treatment (R1881) upregulates KGF promoter activity 6–11 fold in LNCaP cells, with the androgen-responsive element located in the region -900 to -1200 upstream of the transcription start site.","method":"Promoter deletion constructs, transient transfection luciferase assays in LNCaP cells, transcription start site mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter dissection with deletion constructs in relevant cell line, single lab","pmids":["8607856"],"is_preprint":false},{"year":1997,"finding":"KGF prevents H2O2-induced increases in airway epithelial cell permeability through a PKC-dependent mechanism that stabilizes the F-actin cytoskeleton; calphostin C (PKC inhibitor) abolished both KGF-mediated basal barrier enhancement and its protective effect.","method":"Fluorescein isothiocyanate-albumin permeability assay across Transwell monolayers, pharmacological inhibitor (calphostin C), F-actin immunostaining","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with mechanistic inhibitor dissection, single lab, two orthogonal readouts (permeability + cytoskeleton)","pmids":["9142942"],"is_preprint":false},{"year":1997,"finding":"KGF increases DNA repair capacity in irradiated pulmonary epithelial cells through DNA polymerases-α, -δ, and -ε (but not polymerase-β); aphidicolin and butylphenyl dGTP blocked the KGF-mediated reduction in radiation-induced DNA strand breaks, whereas dideoxythymidine triphosphate did not.","method":"137Cs gamma irradiation, alkaline DNA unwinding/ethidium bromide fluorescence assay, selective DNA polymerase inhibitors","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional DNA repair assay with pharmacological dissection of polymerase involvement, single lab","pmids":["9227520"],"is_preprint":false},{"year":1998,"finding":"KGF activates Ras-MAPK (p42/p44 ERK) pathway in human corneal epithelial cells; KGF did not activate the Jak-STAT cascade (STAT1, STAT3, Jak1). Unlike HGF, KGF did not induce phosphorylation of adapter protein Shc or receptor coimmunoprecipitation with Grb2/Sos1.","method":"Immunoprecipitation, Western blot for MAPK activation, gel retardation/EMSA, kinase inhibitors (PD098059, calphostin C, genistein)","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathway assessments with inhibitors and IP in corneal epithelial cells, single lab","pmids":["9660480"],"is_preprint":false},{"year":1999,"finding":"FGF7 and FGF10 directly induce the apical ectodermal ridge (AER) in chick embryos, activating Fgf8 expression in cultured flank ectoderm without mesoderm; FGF7 and FGF10 but not FGF1, -2, or -4 induced ectopic AER in dorsal median ectoderm.","method":"Ectopic bead implantation in chick embryos, ectoderm explant culture without mesoderm, in situ hybridization for Fgf8","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vivo and ex vivo functional assay with molecular marker readout, distinguishes FGF7/10 from other FGF family members","pmids":["10373311"],"is_preprint":false},{"year":1999,"finding":"FGF7 triggers invasive potential and anchorage-independent growth in human prostatic epithelial cells via an autocrine loop; FGF7-transfected PNT1A cells overexpressed MMP-1 and uPA, and invasion was specifically blocked by FGF7-neutralizing antibody.","method":"Stable cDNA transfection, extracellular matrix invasion assay, soft agar growth assay, neutralizing antibody, Western blot for MMP-1 and uPA","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function + neutralizing antibody in defined cell line, single lab, multiple orthogonal assays","pmids":["10389758"],"is_preprint":false},{"year":1999,"finding":"Lens-specific overexpression of KGF (FGF7) in transgenic mice caused hyperproliferation of embryonic corneal epithelial cells and their differentiation into functional lacrimal gland-like tissues, demonstrating that KGF receptor stimulation in surface ectoderm is sufficient to alter cell fate toward lacrimal gland.","method":"Transgenic mouse overexpression (lens-specific promoter), histology, immunohistochemistry","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function transgene with defined phenotypic outcome (cell fate change), single lab","pmids":["10525187"],"is_preprint":false},{"year":2001,"finding":"KGF activates PI3K and its downstream target p70 S6 kinase in corneal epithelial cells; PI3K inhibitor wortmannin, PKC inhibitor calphostin C, and rapamycin all blocked KGF-induced p70 S6K activation and KGF-stimulated corneal epithelial wound healing in an organ culture model. MEK1 inhibitor PD98059 had no effect on p70 S6K activation.","method":"PI3K activity assay, p70 S6K phosphorylation/activity assay, pharmacological inhibitors, corneal organ culture wound healing model","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assays plus functional wound healing readout with pharmacological pathway dissection, single lab","pmids":["11446769"],"is_preprint":false},{"year":2002,"finding":"Dermatan sulfate (chondroitin sulfate B), the predominant glycosaminoglycan in skin, is the principal cofactor for FGF7 activity in wounds; dermatan sulfate enabled FGF7-dependent KGFR (FGFR2 IIIb) binding, MAPK phosphorylation, and proliferation of BaF/KGFR cells and normal keratinocytes. Heparan sulfate and chondroitin sulfate A/C did not support FGF7 activity.","method":"Cell proliferation assay (BaF/KGFR lymphoid cells and keratinocytes), radiolabeled FGF7 binding assay, MAPK phosphorylation Western blot, comparative GAG panel","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined GAG species, receptor binding assay, and signaling readout; multiple orthogonal methods","pmids":["12215437"],"is_preprint":false},{"year":2003,"finding":"KGF-induced activation of the Akt (PI3K) signaling axis mediates protection of lung alveolar epithelial cells from hyperoxia-induced cell death; dominant-negative Akt blocked KGF-mediated epithelial cell survival in vitro and in vivo, and the protective effect was selective for epithelial (not endothelial) cells consistent with selective KGFR expression.","method":"Tetracycline-inducible transgenic lung-specific KGF expression, dominant-negative Akt transfection, in vitro and in vivo hyperoxia cell death assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — inducible transgenic system plus dominant-negative mutant validation in vivo and in vitro, multiple orthogonal approaches","pmids":["12732722"],"is_preprint":false},{"year":2003,"finding":"FGF7-induced breast cancer cell motility requires Grb2 and ERK1/2 (but not Akt) downstream of KGFR tyrosine kinase activation; Grb2 knockdown and ERK1/2 inhibition (PD98059) suppressed KGF-induced motility, while wortmannin (PI3K/Akt inhibitor) did not.","method":"Time-lapse video microscopy, culture wound assay, Grb2 antisense knockdown, pharmacological inhibitors (genistein, PD98059, wortmannin)","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitor approaches plus target knockdown with motility readout, single lab","pmids":["15672868"],"is_preprint":false},{"year":2003,"finding":"Structure-based mutagenesis identified specific FGF7 residues (β4/β5 loop, Asp63, Leu142, Arg65) that are required for interaction with the unique exon IIIb region of FGFR2IIIb; mutations at these residues reduced receptor binding affinity and biological activity, explaining FGF7's exclusive specificity for FGFR2IIIb.","method":"Computational structural modeling of FGFR2IIIb/FGF7 complex, site-directed mutagenesis, receptor binding affinity measurements, biological activity assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided mutagenesis with receptor binding and functional validation, multiple mutants tested","pmids":["14527678"],"is_preprint":false},{"year":2005,"finding":"KGF-induced proliferation in pancreatic ductal cells is mediated through the MEK-ERK1/2 pathway; KGF-induced ductal cell differentiation (PDX1 and Glut2 expression) is mediated through PI3K/AKT. Inactivation of MEK/ERK by pharmacological inhibitor or antisense morpholino-oligonucleotides abolished KGF-induced duct cell proliferation both in vitro and in vivo.","method":"BrdU incorporation (in vitro and in vivo), pharmacological MEK inhibitor, antisense morpholino-oligonucleotides against MEK1, immunolocalization of PDX1/Glut2, PI3K inhibition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods to block ERK (inhibitor + antisense) with functional proliferation readout, single lab","pmids":["19266047"],"is_preprint":false},{"year":2005,"finding":"KGF induces lipogenesis in pulmonary epithelial cells (H292) via PI3K and JNK signaling pathways converging on SREBP-1 transcription factor, which in turn drives expression of FAS and SCD-1; dominant-negative SREBP-1 adenovirus blocked KGF effects on FAS and SCD-1; mutation of the SREBP-1 binding site in SCD-1 promoter abolished KGF induction.","method":"Pharmacological inhibitors (LY294002, SP600125, PD98059), luciferase promoter constructs, adenovirus-mediated dominant-negative SREBP-1 overexpression, Western blot for Akt/S6K/JNK/ERK activation","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal approaches (inhibitors, promoter mutagenesis, dominant-negative viral transduction) in single mechanistic study","pmids":["16162944"],"is_preprint":false},{"year":2007,"finding":"FGF7-induced MAPK(ERK1,2) activation in mammary epithelium is transient (15 min) and promotes growth without branching, whereas TGFα induces sustained ERK activation (1 h) sufficient for branching morphogenesis; FGF7 suppresses TGFα-induced MMP-3 and fibronectin expression, dominating over TGFα when both are applied simultaneously.","method":"Ex vivo mammary explant culture, ERK1/2 activity time-course assays, morphological analysis of branching, inhibitor experiments, keratin-6 immunostaining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ex vivo reconstitution system with precise kinetic signaling measurements, multiple morphogenetic and molecular readouts","pmids":["17448457"],"is_preprint":false},{"year":2007,"finding":"KGF signaling in thymic epithelial cells (TECs) activates p53 and NF-κB pathways, induces BMP2, BMP4, Wnt5b, and Wnt10b expression, and canonical BMP pathway signaling is required for KGF effects on TEC expansion and T-cell development.","method":"In vivo KGF administration to mice, flow cytometry of thymic subsets, gene expression analysis, pathway inhibition studies","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional system with pathway analysis and gene expression readouts, single lab","pmids":["17213286"],"is_preprint":false},{"year":2007,"finding":"KGF maintains the alveolar type II (AT2) cell phenotype through JNK (c-Jun N-terminal kinase) activation; JNK inhibition (but not ERK1/2 or p38 inhibition) abolished KGF-mediated maintenance of AT2 phenotype markers (p180). Overexpression of JNKK2 (upstream JNK kinase) increased c-Jun activation and promoted retention of AT2 markers.","method":"Primary rat AEC culture, selective MAPK inhibitors, JNKK2 overexpression, AT2/AT1 phenotype markers (p180, AQP5, VIIIB2), microarray","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic dissection of MAPK pathways with phenotypic readout, single lab","pmids":["17872496"],"is_preprint":false},{"year":2007,"finding":"KGF increases integrin α5 expression in keratinocytes through ERK1/2-dependent phosphorylation of the C/EBP-β transcription factor; dominant-negative C/EBP-β inhibited α5 promoter activity and siRNA knockdown of C/EBP-β diminished integrin α5 expression.","method":"Promoter reporter assays, ERK1/2 inhibition, dominant-negative C/EBP-β expression, C/EBP-β siRNA knockdown, Western blot, 3D epidermis tissue analogue","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter studies with genetic knockdown and dominant-negative validation, single lab","pmids":["17596295"],"is_preprint":false},{"year":2009,"finding":"KGF (FGF7)/FGFR2IIIb signaling inhibits hair follicle induction and promotes interfollicular epidermal fate; KGF blocked follicle formation in embryonic skin organ culture in a time- and dose-dependent manner, and downstream molecular markers showed epidermal differentiation was promoted at the expense of hair follicle fate.","method":"Embryonic skin organ culture, growth factor treatment, microarray profiling, molecular marker analysis, KGFR/EGFR expression mapping","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo organ culture with dose-dependent effects, molecular markers, and microarray, single lab","pmids":["19474150"],"is_preprint":false},{"year":2012,"finding":"Increased KGF expression in fibroblasts promotes cutaneous fibrosis through a double paracrine mechanism: KGF stimulates keratinocytes to produce and secrete oncostatin M (OSM), which in turn activates fibroblasts; OSM-mediated STAT3 phosphorylation upregulates urokinase plasminogen activator, increasing collagen type I-α1 expression and fibroblast migration.","method":"KGF stimulation of keratinocytes, conditioned medium experiments, ELISA for OSM, Western blot for STAT3 phosphorylation, collagen expression, migration assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with conditioned medium, signaling readouts, and functional assays, single lab","pmids":["23096718"],"is_preprint":false},{"year":2014,"finding":"FGF7 induces autophagy in human keratinocytes through a PI3K-AKT-MTOR-independent mechanism, stimulating autophagosome formation; upon prolonged stimulation FGF7 also accelerates autophagosome turnover. Autophagy was required for FGF7-mediated early keratinocyte differentiation, as BECN1 and ATG5 depletion counteracted FGF7-induced KRT1 upregulation.","method":"Biochemical autophagy markers (LC3, p62), quantitative fluorescence microscopy, autophagosome-lysosome fusion block, siRNA depletion of BECN1 and ATG5, PI3K/AKT/mTOR inhibitors","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (inhibitors + genetic knockdown + quantitative imaging), single lab","pmids":["24577098"],"is_preprint":false},{"year":2014,"finding":"FGF7 is selectively targeted to inhibitory postsynaptic sites in hippocampal neurons where it acts as a presynaptic organizer for inhibitory synapse differentiation; inhibitory synaptic targeting of FGF7 requires the motor protein KIF5 and adaptor gephyrin; time-lapse imaging showed FGF7 co-moves with gephyrin along microtubules.","method":"Selective synaptic targeting analysis, KIF5 and gephyrin knockdown, time-lapse live imaging, co-transport assays, SAP102/PSD95 knockdown effects on FGF7 localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — live imaging + genetic knockdown of motor/adaptor proteins + functional synapse assay, multiple orthogonal approaches","pmids":["25431136"],"is_preprint":false},{"year":2015,"finding":"GLP-1 receptor signaling promotes intestinal mucosal growth through a mechanism requiring Fgf7; exendin-4 failed to increase intestinal growth in Fgf7-knockout mice, and exendin-4 increased Fgf7 expression in colonic polyps; exendin-4 and Fgf7 regulated an overlapping set of intestinal growth genes.","method":"Fgf7 knockout mice, exendin-4 treatment, Apc(Min/+) mouse model, gene expression analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Fgf7 KO abolishes GLP-1R effect) independently confirmed in multiple mouse models with molecular readouts","pmids":["25738454"],"is_preprint":false},{"year":2017,"finding":"FGF7/FGFR2 signaling promotes invasion and migration of human gastric cancer cells through upregulation of thrombospondin-1 (THBS1) via the PI3K/Akt/mTOR pathway; FGFR2 knockdown partially suppressed FGF7-induced invasion/migration, and THBS1 knockdown similarly reduced these effects.","method":"FGFR2 knockdown, THBS1 knockdown, in vitro invasion/migration assays, PI3K/Akt/mTOR pathway inhibition, Western blot","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual target knockdown with functional assays and pathway inhibition, single lab","pmids":["28339036"],"is_preprint":false},{"year":2018,"finding":"FGF7 promotes osteocyte cell process formation and gap junctional communication through connexin43 (Cx43) via FGF7-induced cytoplasmic accumulation and nuclear translocation of β-catenin; β-catenin signaling mediated FGF7's upregulation of Cx43 expression in MLO-Y4 osteocyte cells.","method":"qRT-PCR, Western blot, immunofluorescence for Cx43 and β-catenin localization, nuclear fractionation, cell process morphology analysis in MLO-Y4 cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with localization and functional readouts, single lab","pmids":["30287900"],"is_preprint":false},{"year":2019,"finding":"KGF-1 accelerates wound contraction through a double-paracrine mechanism: KGF-1 stimulates keratinocytes to produce TGF-β1, which then activates fibroblasts; this leads to increased Col-I, p-Smad2, p-Smad3, and α-SMA expression. TGF-β1-neutralizing antibody attenuated the KGF-1-induced contractile capacity of fibroblast-populated collagen lattices.","method":"Keratinocyte-fibroblast co-culture, ELISA for TGF-β1, fibroblast-populated collagen lattice contraction assay, TGF-β1 neutralizing antibody, Western blot for Smad pathway components, diabetic rat wound model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection with neutralizing antibody + in vitro and in vivo validation, single lab","pmids":["30894415"],"is_preprint":false},{"year":2019,"finding":"FGF7 structural subfamily analysis: members of the FGF7 subfamily (FGF3, FGF7, FGF10, FGF22) achieve restricted specificity for FGFR1b/FGFR2b by engaging specific contacts with two alternatively spliced loop regions in the immunoglobulin-like domain 3 (D3) of these receptors; weak basal receptor-binding affinity further constrains specificity; heparin sulfate co-receptor affinity differences among the four members contribute to their disparate biological activities.","method":"Structural analysis review (compilation of crystal structures and mutagenesis data from the field)","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — synthesis of structural and mutagenesis data; review article summarizing prior crystallographic/mutagenesis work rather than a single new experiment","pmids":["30809251"],"is_preprint":false},{"year":2021,"finding":"FGF7 promotes osteoblast dendrite elongation and functional gap junction formation by increasing E11 expression; E11 directly interacted with Cx43 in primary osteoblasts; MAPK and PI3K-AKT pathways were involved in FGF7-mediated E11 upregulation and cell process formation.","method":"Co-immunoprecipitation (E11-Cx43 interaction), Western blot, immunofluorescence, pathway inhibitors (MAPK, PI3K-AKT), osteoblast morphology analysis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction (Co-IP) plus pathway inhibition and functional readout, single lab","pmids":["34671204"],"is_preprint":false},{"year":2022,"finding":"FGF7/FGFR2 signaling abolishes progesterone receptor (PR)-mediated modulation of estrogen receptor (ER) activity in luminal breast cancer; FGF7/FGFR2 signaling regulated ER and PR expression and activity, increased ER-PR complex formation, reversed P4-triggered ER-dependent gene deregulation, and required JunB as a prerequisite for abrogating P4-induced growth inhibition.","method":"3D cell growth assays, hormone receptor expression and activity assays (ER/PR), ER-PR co-immunoprecipitation, gene expression analysis, JunB functional requirement assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for ER-PR complexes, functional 3D growth assays, molecular pathway analysis, single lab","pmids":["35726195"],"is_preprint":false},{"year":2022,"finding":"SOX9, activated by WNT3A via TCF7, enhances FGF7 transcription and expression in cholangiocarcinoma; secreted FGF7 activates FGFR2 phosphorylation in an autocrine pathway promoting CCA proliferation and pemigatinib resistance.","method":"mRNA sequencing, in vitro/in vivo validation, WNT3A stimulation, SOX9 overexpression/knockdown, FGFR2 phosphorylation assay, autocrine secretion measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss of function with signaling readouts in vitro and in vivo, single lab","pmids":["35428876"],"is_preprint":false},{"year":2024,"finding":"Fibro-adipogenic progenitors (FAPs) interact with muscle satellite cells (MuSCs) via FGF7-FGFR2 signaling to promote MuSC proliferation; FGFR2 knockdown in MuSCs abolished the pro-proliferative effects of exogenous FGF7; FGF7 administration increased satellite cell proliferation and enhanced muscle regeneration in injury and aging models.","method":"Single-cell RNA sequencing, CellChat cell-cell communication analysis, FGFR2 knockdown, EdU proliferation assays, cardiotoxin injury model, d-galactose aging model, in vivo muscle function assays","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq for interaction identification, FGFR2 knockdown validates receptor requirement, multiple in vitro and in vivo functional assays","pmids":["38751367"],"is_preprint":false},{"year":2024,"finding":"Cancer-associated fibroblast-derived FGF7 promotes ovarian cancer progression by inhibiting ubiquitination and degradation of HIF-1α via FGFR2 interaction, activating the FGF7/HIF-1α/EMT axis; neutralizing antibodies against FGF7 substantially reduced tumor growth in vivo.","method":"In vitro invasion/migration/proliferation assays, single-cell transcriptomic analysis, HIF-1α ubiquitination assay, FGFR2 interaction studies, in vivo neutralizing antibody treatment","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic assay (HIF-1α ubiquitination) plus in vivo antibody neutralization, single lab","pmids":["38491511"],"is_preprint":false}],"current_model":"FGF7 (KGF) is a mesenchyme-derived, heparin-binding growth factor that signals exclusively through FGFR2 IIIb (KGFR) on epithelial cells, with dermatan sulfate serving as the principal physiological co-receptor in skin; upon receptor activation FGF7 engages Ras-MAPK (ERK1/2), PI3K-Akt, and JNK pathways in a context-dependent manner to drive epithelial proliferation, survival (via Akt), differentiation (via JNK/c-Jun in alveolar cells, SREBP-1 in lipogenesis, β-catenin in bone), and migration (via Grb2-ERK1/2 and integrin α5 upregulation through C/EBP-β); it acts as a presynaptic organizer for inhibitory synapses in neurons (transported by KIF5/gephyrin to inhibitory postsynaptic sites), promotes wound contraction through a double-paracrine TGF-β1/Smad cascade, and can stimulate an autocrine FGF7-FGFR2 loop in certain cancers that activates MAPK, PI3K/Akt/mTOR, and HIF-1α to drive invasion and therapy resistance."},"narrative":{"mechanistic_narrative":"FGF7 (KGF) is a secreted, heparin-binding growth factor that drives epithelial proliferation, survival, differentiation, and migration by signaling through a single high-affinity receptor, FGFR2 IIIb (KGFR), engaged with exquisite specificity through residues in its β4/β5 loop and contacts with the alternatively spliced D3 region of the receptor [PMID:1846048, PMID:14527678, PMID:30809251]. This receptor selectivity restricts FGF7's action to epithelia, and its activity additionally depends on a glycosaminoglycan co-receptor: in skin, dermatan sulfate rather than heparan sulfate is the principal physiological cofactor enabling FGF7-dependent receptor binding and signaling [PMID:12215437, PMID:7528211]. Receptor engagement is read out through several context-dependent intracellular cascades — Ras-MAPK/ERK1/2 for proliferation and motility [PMID:9660480, PMID:15672868, PMID:19266047], PI3K-Akt(-S6K) for epithelial survival and differentiation [PMID:11446769, PMID:12732722, PMID:19266047], and JNK for maintenance of alveolar type II cell identity [PMID:17872496] — with these arms feeding distinct transcriptional effectors (SREBP-1 for lipogenesis, C/EBP-β for integrin α5, β-catenin in osteocytes) [PMID:16162944, PMID:17596295, PMID:30287900]. At the tissue level, FGF7-FGFR2 IIIb signaling is required for epidermal morphogenesis and wound reepithelialization [PMID:7973639], directs surface-ectoderm cell fate including apical ectodermal ridge induction and epidermal-versus-follicle choice [PMID:10373311, PMID:19474150], and orchestrates fibrosis and wound contraction through double-paracrine loops in which FGF7 stimulates keratinocytes to secrete OSM or TGF-β1 that then activate fibroblasts [PMID:23096718, PMID:30894415]. Beyond epithelia, FGF7 acts as a presynaptic organizer of inhibitory synapses, being transported by KIF5/gephyrin to inhibitory postsynaptic sites [PMID:25431136], and as a stromal mediator of regeneration that drives muscle satellite-cell proliferation [PMID:38751367]. In cancer, autocrine and stromal FGF7-FGFR2 loops promote invasion, EMT, and therapy resistance via MMP/uPA induction, PI3K/Akt/mTOR-THBS1, and HIF-1α stabilization [PMID:10389758, PMID:28339036, PMID:35428876, PMID:38491511].","teleology":[{"year":1991,"claim":"Established that KGF/FGF7 acts through its own dedicated high-affinity tyrosine kinase receptor distinct from the bFGF receptor, defining the ligand-receptor axis that all later mechanism rests on.","evidence":"Expression cDNA cloning and ligand-binding competition with transformation assay in NIH/3T3 fibroblasts","pmids":["1846048"],"confidence":"High","gaps":["Did not define which epithelial cell types depend on this receptor in vivo","Structural basis of specificity not yet resolved"]},{"year":1994,"claim":"Demonstrated that KGFR signaling in basal keratinocytes is physiologically required for epidermal morphogenesis and wound reepithelialization, moving FGF7 from a biochemical activity to an in vivo tissue function.","evidence":"Dominant-negative KGFR transgene in mouse keratinocytes with skin histology and wound-healing assays","pmids":["7973639"],"confidence":"High","gaps":["Dominant-negative blocks all FGFR2 IIIb ligands, not FGF7 specifically","Downstream signaling not dissected"]},{"year":1994,"claim":"Showed that cell-surface heparan sulfate modulates rather than universally promotes FGF7 binding, raising the question of which glycosaminoglycan is the true physiological co-receptor.","evidence":"Radioligand binding with chlorate/heparinase treatment in KGFR-expressing cell lines","pmids":["7528211"],"confidence":"High","gaps":["Identity of the physiological co-receptor not resolved here","Low-affinity binding site left unidentified"]},{"year":2002,"claim":"Identified dermatan sulfate as the principal skin glycosaminoglycan cofactor enabling FGF7-dependent receptor binding and signaling, resolving the co-receptor question for wounds.","evidence":"GAG-panel reconstitution with radiolabeled FGF7 binding, MAPK phosphorylation, and proliferation in BaF/KGFR cells and keratinocytes","pmids":["12215437"],"confidence":"High","gaps":["Whether dermatan sulfate serves as co-receptor in non-skin tissues unknown","Structural geometry of the FGF7-dermatan-receptor complex not defined"]},{"year":2003,"claim":"Provided the structural basis for FGF7's exclusive FGFR2 IIIb specificity by mapping ligand residues that contact the exon-IIIb region, explaining receptor selectivity at atomic resolution.","evidence":"Structure-based mutagenesis of FGF7 with receptor binding-affinity and activity assays","pmids":["14527678"],"confidence":"High","gaps":["No experimental co-crystal structure reported in this entry","Contribution of GAG to specificity addressed only later"]},{"year":2001,"claim":"Dissected the downstream signaling logic, showing FGF7 activates ERK-MAPK, PI3K-Akt/S6K, and JNK arms that are deployed differentially for proliferation, survival, and differentiation in distinct epithelia.","evidence":"Pharmacological and genetic pathway dissection (wortmannin, rapamycin, PD98059, dominant-negative Akt, JNKK2) with proliferation/survival/differentiation readouts across corneal, pancreatic, alveolar, and breast cells","pmids":["11446769","12732722","15672868","19266047","17872496","9660480"],"confidence":"High","gaps":["What determines pathway selection in a given cell type remains unclear","Receptor-proximal adapter usage (Shc/Grb2/Sos) appears context-dependent and incompletely resolved"]},{"year":2005,"claim":"Connected FGF7 signaling arms to specific transcription-factor effectors, showing PI3K/JNK→SREBP-1 drives lipogenic gene expression and ERK→C/EBP-β drives integrin α5, defining transcriptional outputs.","evidence":"Promoter reporter mutagenesis, dominant-negative SREBP-1/C/EBP-β, and siRNA in pulmonary and keratinocyte models","pmids":["16162944","20"],"confidence":"High","gaps":["Effector usage may be cell-type restricted","Integration of multiple transcription factors not modeled"]},{"year":1999,"claim":"Established FGF7's role in surface-ectoderm fate decisions, including apical ectodermal ridge induction and cell-fate reprogramming, distinguishing it functionally from other FGF family members.","evidence":"Chick bead implantation/ectoderm explants with Fgf8 in situ and lens-specific KGF transgenic mice","pmids":["10373311","10525187"],"confidence":"High","gaps":["Molecular mediators of fate change not fully defined","Relationship to FGFR2 IIIb signaling arms not dissected here"]},{"year":2007,"claim":"Revealed signaling kinetics as a determinant of morphogenetic outcome — transient FGF7-driven ERK promotes growth without branching and dominates over branching-inducing TGFα signals.","evidence":"Ex vivo mammary explant culture with ERK time-course and morphological/molecular readouts","pmids":["17448457"],"confidence":"High","gaps":["Mechanism setting ERK duration not identified","Generalizability to other branched epithelia untested"]},{"year":2014,"claim":"Identified FGF7 as a presynaptic organizer of inhibitory synapses delivered to postsynaptic sites by motor/adaptor machinery, extending FGF7 function beyond epithelia into neurons.","evidence":"Live imaging and KIF5/gephyrin knockdown in hippocampal neurons with synapse-targeting assays","pmids":["25431136"],"confidence":"High","gaps":["Receptor mediating the synaptic-organizing activity not defined here","In vivo significance for inhibitory circuits untested"]},{"year":2012,"claim":"Defined double-paracrine epithelial-mesenchymal loops (KGF→keratinocyte→OSM/TGF-β1→fibroblast) as the mechanism for FGF7-driven fibrosis and wound contraction.","evidence":"Conditioned-medium experiments, neutralizing antibodies, STAT3/Smad signaling readouts, and collagen-lattice contraction with in vivo wound models","pmids":["23096718","30894415"],"confidence":"Medium","gaps":["Single-lab mechanisms","Relative contributions of OSM versus TGF-β1 loops in 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counteracts the effect of progesterone in luminal breast cancer.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35726195","citation_count":19,"is_preprint":false},{"pmid":"30155985","id":"PMC_30155985","title":"TGF beta inhibits HGF, FGF7, and FGF10 expression in normal and IPF lung fibroblasts.","date":"2018","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/30155985","citation_count":19,"is_preprint":false},{"pmid":"35783154","id":"PMC_35783154","title":"circCCT3 Enhances Invasion and Epithelial-Mesenchymal Transition (EMT) of Non-Small-Cell Lung Cancer (NSCLC) via the miR-107/Wnt/FGF7 Axis.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35783154","citation_count":19,"is_preprint":false},{"pmid":"9840508","id":"PMC_9840508","title":"Induction of KGF, basic FGF, and TGFalpha mRNA expression during healing of experimental TM perforations.","date":"1998","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/9840508","citation_count":19,"is_preprint":false},{"pmid":"16142419","id":"PMC_16142419","title":"Comparative genomics on FGF7, FGF10, FGF22 orthologs, and identification of fgf25.","date":"2005","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16142419","citation_count":19,"is_preprint":false},{"pmid":"31490279","id":"PMC_31490279","title":"Comparative Analysis of KGF-2 and bFGF in Prevention of Excessive Wound Healing and Scar Formation in a Corneal Alkali Burn Model.","date":"2019","source":"Cornea","url":"https://pubmed.ncbi.nlm.nih.gov/31490279","citation_count":19,"is_preprint":false},{"pmid":"17596295","id":"PMC_17596295","title":"KGF promotes integrin alpha5 expression through CCAAT/enhancer-binding protein-beta.","date":"2007","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17596295","citation_count":18,"is_preprint":false},{"pmid":"37569486","id":"PMC_37569486","title":"BFNB Enhances Hair Growth in C57BL/6 Mice through the Induction of EGF and FGF7 Factors and the PI3K-AKT-β-Catenin Pathway.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37569486","citation_count":18,"is_preprint":false},{"pmid":"25138153","id":"PMC_25138153","title":"In vivo over-expression of KGF mimic human middle ear cholesteatoma.","date":"2014","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/25138153","citation_count":18,"is_preprint":false},{"pmid":"10911393","id":"PMC_10911393","title":"Pattern of expression of the KGF receptor and its ligands KGF and FGF-10 during postnatal mouse mammary gland development.","date":"2000","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/10911393","citation_count":18,"is_preprint":false},{"pmid":"15809711","id":"PMC_15809711","title":"FGF7-like gene is associated with pericentric inversion of chromosome 9, and FGF7 is involved in the development of ovarian cancer.","date":"2005","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15809711","citation_count":18,"is_preprint":false},{"pmid":"12653837","id":"PMC_12653837","title":"Keratinocyte growth factor (KGF) decreases ICAM-1 and VCAM-1 cell expression on bronchial epithelial cells.","date":"2003","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12653837","citation_count":18,"is_preprint":false},{"pmid":"16827106","id":"PMC_16827106","title":"Keratinocyte growth factor (KGF) induces tamoxifen (Tam) resistance in human breast cancer MCF-7 cells.","date":"2006","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16827106","citation_count":18,"is_preprint":false},{"pmid":"18368565","id":"PMC_18368565","title":"Keratinocyte growth factor receptor (KGF-R) in cholesteatoma tissue.","date":"2008","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/18368565","citation_count":17,"is_preprint":false},{"pmid":"9564867","id":"PMC_9564867","title":"Mammogenic hormones differentially modulate keratinocyte growth factor (KGF)-induced proliferation and KGF receptor expression in cultured mouse mammary gland epithelium.","date":"1998","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9564867","citation_count":17,"is_preprint":false},{"pmid":"22443411","id":"PMC_22443411","title":"Potential dual role of KGF/KGFR as a target option in novel therapeutic strategies for the treatment of cancers and mucosal damages.","date":"2012","source":"Expert opinion on therapeutic 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tyrosine kinase receptor (KGFR/FGFR2 IIIb) that is distinct from the basic FGF receptor; expression cloning in NIH/3T3 fibroblasts demonstrated acquisition of specific high-affinity KGF binding sites and transformation via an autocrine loop.\",\n      \"method\": \"Expression cDNA cloning, ligand binding competition assays, focus formation/transformation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct receptor cloning with functional validation (binding, transformation), foundational study replicated across many subsequent papers\",\n      \"pmids\": [\"1846048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"KGF receptor signaling in basal keratinocytes is required for normal epidermal morphogenesis and reepithelialization of wounds; dominant-negative KGFR transgene in mice caused epidermal atrophy, hair follicle abnormalities, dermal hyperthickening, and substantially delayed wound reepithelialization with reduced keratinocyte proliferation at wound edges.\",\n      \"method\": \"Dominant-negative transgene expression in mouse basal keratinocytes, skin histology, wound healing assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function (dominant-negative transgene) with defined cellular phenotype (epidermal atrophy, impaired wound healing), widely replicated\",\n      \"pmids\": [\"7973639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Cell-associated heparan sulfates differentially modulate KGF binding to KGFR: heparin inhibits KGF binding to KGFR whereas it enhances aFGF binding to the same receptor; removal of cell-surface heparan sulfates (chlorate treatment or heparinase) enhances KGF high-affinity binding ~2-fold. KGF also interacts with an unidentified low-affinity binding site unaffected by heparan sulfate removal.\",\n      \"method\": \"Radioligand binding assays, sodium chlorate treatment to block proteoglycan sulfation, heparinase/heparitinase digestion, competition binding in L6E9 cells expressing KGFR and Balb/MK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in defined cell lines with multiple orthogonal biochemical methods and mechanistic controls\",\n      \"pmids\": [\"7528211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The KGF/FGF7 promoter is directly regulated by androgens; androgen treatment (R1881) upregulates KGF promoter activity 6–11 fold in LNCaP cells, with the androgen-responsive element located in the region -900 to -1200 upstream of the transcription start site.\",\n      \"method\": \"Promoter deletion constructs, transient transfection luciferase assays in LNCaP cells, transcription start site mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter dissection with deletion constructs in relevant cell line, single lab\",\n      \"pmids\": [\"8607856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KGF prevents H2O2-induced increases in airway epithelial cell permeability through a PKC-dependent mechanism that stabilizes the F-actin cytoskeleton; calphostin C (PKC inhibitor) abolished both KGF-mediated basal barrier enhancement and its protective effect.\",\n      \"method\": \"Fluorescein isothiocyanate-albumin permeability assay across Transwell monolayers, pharmacological inhibitor (calphostin C), F-actin immunostaining\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with mechanistic inhibitor dissection, single lab, two orthogonal readouts (permeability + cytoskeleton)\",\n      \"pmids\": [\"9142942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KGF increases DNA repair capacity in irradiated pulmonary epithelial cells through DNA polymerases-α, -δ, and -ε (but not polymerase-β); aphidicolin and butylphenyl dGTP blocked the KGF-mediated reduction in radiation-induced DNA strand breaks, whereas dideoxythymidine triphosphate did not.\",\n      \"method\": \"137Cs gamma irradiation, alkaline DNA unwinding/ethidium bromide fluorescence assay, selective DNA polymerase inhibitors\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional DNA repair assay with pharmacological dissection of polymerase involvement, single lab\",\n      \"pmids\": [\"9227520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"KGF activates Ras-MAPK (p42/p44 ERK) pathway in human corneal epithelial cells; KGF did not activate the Jak-STAT cascade (STAT1, STAT3, Jak1). Unlike HGF, KGF did not induce phosphorylation of adapter protein Shc or receptor coimmunoprecipitation with Grb2/Sos1.\",\n      \"method\": \"Immunoprecipitation, Western blot for MAPK activation, gel retardation/EMSA, kinase inhibitors (PD098059, calphostin C, genistein)\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathway assessments with inhibitors and IP in corneal epithelial cells, single lab\",\n      \"pmids\": [\"9660480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FGF7 and FGF10 directly induce the apical ectodermal ridge (AER) in chick embryos, activating Fgf8 expression in cultured flank ectoderm without mesoderm; FGF7 and FGF10 but not FGF1, -2, or -4 induced ectopic AER in dorsal median ectoderm.\",\n      \"method\": \"Ectopic bead implantation in chick embryos, ectoderm explant culture without mesoderm, in situ hybridization for Fgf8\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vivo and ex vivo functional assay with molecular marker readout, distinguishes FGF7/10 from other FGF family members\",\n      \"pmids\": [\"10373311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FGF7 triggers invasive potential and anchorage-independent growth in human prostatic epithelial cells via an autocrine loop; FGF7-transfected PNT1A cells overexpressed MMP-1 and uPA, and invasion was specifically blocked by FGF7-neutralizing antibody.\",\n      \"method\": \"Stable cDNA transfection, extracellular matrix invasion assay, soft agar growth assay, neutralizing antibody, Western blot for MMP-1 and uPA\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function + neutralizing antibody in defined cell line, single lab, multiple orthogonal assays\",\n      \"pmids\": [\"10389758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Lens-specific overexpression of KGF (FGF7) in transgenic mice caused hyperproliferation of embryonic corneal epithelial cells and their differentiation into functional lacrimal gland-like tissues, demonstrating that KGF receptor stimulation in surface ectoderm is sufficient to alter cell fate toward lacrimal gland.\",\n      \"method\": \"Transgenic mouse overexpression (lens-specific promoter), histology, immunohistochemistry\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function transgene with defined phenotypic outcome (cell fate change), single lab\",\n      \"pmids\": [\"10525187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"KGF activates PI3K and its downstream target p70 S6 kinase in corneal epithelial cells; PI3K inhibitor wortmannin, PKC inhibitor calphostin C, and rapamycin all blocked KGF-induced p70 S6K activation and KGF-stimulated corneal epithelial wound healing in an organ culture model. MEK1 inhibitor PD98059 had no effect on p70 S6K activation.\",\n      \"method\": \"PI3K activity assay, p70 S6K phosphorylation/activity assay, pharmacological inhibitors, corneal organ culture wound healing model\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assays plus functional wound healing readout with pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"11446769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Dermatan sulfate (chondroitin sulfate B), the predominant glycosaminoglycan in skin, is the principal cofactor for FGF7 activity in wounds; dermatan sulfate enabled FGF7-dependent KGFR (FGFR2 IIIb) binding, MAPK phosphorylation, and proliferation of BaF/KGFR cells and normal keratinocytes. Heparan sulfate and chondroitin sulfate A/C did not support FGF7 activity.\",\n      \"method\": \"Cell proliferation assay (BaF/KGFR lymphoid cells and keratinocytes), radiolabeled FGF7 binding assay, MAPK phosphorylation Western blot, comparative GAG panel\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined GAG species, receptor binding assay, and signaling readout; multiple orthogonal methods\",\n      \"pmids\": [\"12215437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KGF-induced activation of the Akt (PI3K) signaling axis mediates protection of lung alveolar epithelial cells from hyperoxia-induced cell death; dominant-negative Akt blocked KGF-mediated epithelial cell survival in vitro and in vivo, and the protective effect was selective for epithelial (not endothelial) cells consistent with selective KGFR expression.\",\n      \"method\": \"Tetracycline-inducible transgenic lung-specific KGF expression, dominant-negative Akt transfection, in vitro and in vivo hyperoxia cell death assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — inducible transgenic system plus dominant-negative mutant validation in vivo and in vitro, multiple orthogonal approaches\",\n      \"pmids\": [\"12732722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FGF7-induced breast cancer cell motility requires Grb2 and ERK1/2 (but not Akt) downstream of KGFR tyrosine kinase activation; Grb2 knockdown and ERK1/2 inhibition (PD98059) suppressed KGF-induced motility, while wortmannin (PI3K/Akt inhibitor) did not.\",\n      \"method\": \"Time-lapse video microscopy, culture wound assay, Grb2 antisense knockdown, pharmacological inhibitors (genistein, PD98059, wortmannin)\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitor approaches plus target knockdown with motility readout, single lab\",\n      \"pmids\": [\"15672868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Structure-based mutagenesis identified specific FGF7 residues (β4/β5 loop, Asp63, Leu142, Arg65) that are required for interaction with the unique exon IIIb region of FGFR2IIIb; mutations at these residues reduced receptor binding affinity and biological activity, explaining FGF7's exclusive specificity for FGFR2IIIb.\",\n      \"method\": \"Computational structural modeling of FGFR2IIIb/FGF7 complex, site-directed mutagenesis, receptor binding affinity measurements, biological activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided mutagenesis with receptor binding and functional validation, multiple mutants tested\",\n      \"pmids\": [\"14527678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KGF-induced proliferation in pancreatic ductal cells is mediated through the MEK-ERK1/2 pathway; KGF-induced ductal cell differentiation (PDX1 and Glut2 expression) is mediated through PI3K/AKT. Inactivation of MEK/ERK by pharmacological inhibitor or antisense morpholino-oligonucleotides abolished KGF-induced duct cell proliferation both in vitro and in vivo.\",\n      \"method\": \"BrdU incorporation (in vitro and in vivo), pharmacological MEK inhibitor, antisense morpholino-oligonucleotides against MEK1, immunolocalization of PDX1/Glut2, PI3K inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods to block ERK (inhibitor + antisense) with functional proliferation readout, single lab\",\n      \"pmids\": [\"19266047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KGF induces lipogenesis in pulmonary epithelial cells (H292) via PI3K and JNK signaling pathways converging on SREBP-1 transcription factor, which in turn drives expression of FAS and SCD-1; dominant-negative SREBP-1 adenovirus blocked KGF effects on FAS and SCD-1; mutation of the SREBP-1 binding site in SCD-1 promoter abolished KGF induction.\",\n      \"method\": \"Pharmacological inhibitors (LY294002, SP600125, PD98059), luciferase promoter constructs, adenovirus-mediated dominant-negative SREBP-1 overexpression, Western blot for Akt/S6K/JNK/ERK activation\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal approaches (inhibitors, promoter mutagenesis, dominant-negative viral transduction) in single mechanistic study\",\n      \"pmids\": [\"16162944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FGF7-induced MAPK(ERK1,2) activation in mammary epithelium is transient (15 min) and promotes growth without branching, whereas TGFα induces sustained ERK activation (1 h) sufficient for branching morphogenesis; FGF7 suppresses TGFα-induced MMP-3 and fibronectin expression, dominating over TGFα when both are applied simultaneously.\",\n      \"method\": \"Ex vivo mammary explant culture, ERK1/2 activity time-course assays, morphological analysis of branching, inhibitor experiments, keratin-6 immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ex vivo reconstitution system with precise kinetic signaling measurements, multiple morphogenetic and molecular readouts\",\n      \"pmids\": [\"17448457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF signaling in thymic epithelial cells (TECs) activates p53 and NF-κB pathways, induces BMP2, BMP4, Wnt5b, and Wnt10b expression, and canonical BMP pathway signaling is required for KGF effects on TEC expansion and T-cell development.\",\n      \"method\": \"In vivo KGF administration to mice, flow cytometry of thymic subsets, gene expression analysis, pathway inhibition studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional system with pathway analysis and gene expression readouts, single lab\",\n      \"pmids\": [\"17213286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF maintains the alveolar type II (AT2) cell phenotype through JNK (c-Jun N-terminal kinase) activation; JNK inhibition (but not ERK1/2 or p38 inhibition) abolished KGF-mediated maintenance of AT2 phenotype markers (p180). Overexpression of JNKK2 (upstream JNK kinase) increased c-Jun activation and promoted retention of AT2 markers.\",\n      \"method\": \"Primary rat AEC culture, selective MAPK inhibitors, JNKK2 overexpression, AT2/AT1 phenotype markers (p180, AQP5, VIIIB2), microarray\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic dissection of MAPK pathways with phenotypic readout, single lab\",\n      \"pmids\": [\"17872496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF increases integrin α5 expression in keratinocytes through ERK1/2-dependent phosphorylation of the C/EBP-β transcription factor; dominant-negative C/EBP-β inhibited α5 promoter activity and siRNA knockdown of C/EBP-β diminished integrin α5 expression.\",\n      \"method\": \"Promoter reporter assays, ERK1/2 inhibition, dominant-negative C/EBP-β expression, C/EBP-β siRNA knockdown, Western blot, 3D epidermis tissue analogue\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter studies with genetic knockdown and dominant-negative validation, single lab\",\n      \"pmids\": [\"17596295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KGF (FGF7)/FGFR2IIIb signaling inhibits hair follicle induction and promotes interfollicular epidermal fate; KGF blocked follicle formation in embryonic skin organ culture in a time- and dose-dependent manner, and downstream molecular markers showed epidermal differentiation was promoted at the expense of hair follicle fate.\",\n      \"method\": \"Embryonic skin organ culture, growth factor treatment, microarray profiling, molecular marker analysis, KGFR/EGFR expression mapping\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo organ culture with dose-dependent effects, molecular markers, and microarray, single lab\",\n      \"pmids\": [\"19474150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Increased KGF expression in fibroblasts promotes cutaneous fibrosis through a double paracrine mechanism: KGF stimulates keratinocytes to produce and secrete oncostatin M (OSM), which in turn activates fibroblasts; OSM-mediated STAT3 phosphorylation upregulates urokinase plasminogen activator, increasing collagen type I-α1 expression and fibroblast migration.\",\n      \"method\": \"KGF stimulation of keratinocytes, conditioned medium experiments, ELISA for OSM, Western blot for STAT3 phosphorylation, collagen expression, migration assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with conditioned medium, signaling readouts, and functional assays, single lab\",\n      \"pmids\": [\"23096718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGF7 induces autophagy in human keratinocytes through a PI3K-AKT-MTOR-independent mechanism, stimulating autophagosome formation; upon prolonged stimulation FGF7 also accelerates autophagosome turnover. Autophagy was required for FGF7-mediated early keratinocyte differentiation, as BECN1 and ATG5 depletion counteracted FGF7-induced KRT1 upregulation.\",\n      \"method\": \"Biochemical autophagy markers (LC3, p62), quantitative fluorescence microscopy, autophagosome-lysosome fusion block, siRNA depletion of BECN1 and ATG5, PI3K/AKT/mTOR inhibitors\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (inhibitors + genetic knockdown + quantitative imaging), single lab\",\n      \"pmids\": [\"24577098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGF7 is selectively targeted to inhibitory postsynaptic sites in hippocampal neurons where it acts as a presynaptic organizer for inhibitory synapse differentiation; inhibitory synaptic targeting of FGF7 requires the motor protein KIF5 and adaptor gephyrin; time-lapse imaging showed FGF7 co-moves with gephyrin along microtubules.\",\n      \"method\": \"Selective synaptic targeting analysis, KIF5 and gephyrin knockdown, time-lapse live imaging, co-transport assays, SAP102/PSD95 knockdown effects on FGF7 localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — live imaging + genetic knockdown of motor/adaptor proteins + functional synapse assay, multiple orthogonal approaches\",\n      \"pmids\": [\"25431136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GLP-1 receptor signaling promotes intestinal mucosal growth through a mechanism requiring Fgf7; exendin-4 failed to increase intestinal growth in Fgf7-knockout mice, and exendin-4 increased Fgf7 expression in colonic polyps; exendin-4 and Fgf7 regulated an overlapping set of intestinal growth genes.\",\n      \"method\": \"Fgf7 knockout mice, exendin-4 treatment, Apc(Min/+) mouse model, gene expression analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Fgf7 KO abolishes GLP-1R effect) independently confirmed in multiple mouse models with molecular readouts\",\n      \"pmids\": [\"25738454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF7/FGFR2 signaling promotes invasion and migration of human gastric cancer cells through upregulation of thrombospondin-1 (THBS1) via the PI3K/Akt/mTOR pathway; FGFR2 knockdown partially suppressed FGF7-induced invasion/migration, and THBS1 knockdown similarly reduced these effects.\",\n      \"method\": \"FGFR2 knockdown, THBS1 knockdown, in vitro invasion/migration assays, PI3K/Akt/mTOR pathway inhibition, Western blot\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual target knockdown with functional assays and pathway inhibition, single lab\",\n      \"pmids\": [\"28339036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FGF7 promotes osteocyte cell process formation and gap junctional communication through connexin43 (Cx43) via FGF7-induced cytoplasmic accumulation and nuclear translocation of β-catenin; β-catenin signaling mediated FGF7's upregulation of Cx43 expression in MLO-Y4 osteocyte cells.\",\n      \"method\": \"qRT-PCR, Western blot, immunofluorescence for Cx43 and β-catenin localization, nuclear fractionation, cell process morphology analysis in MLO-Y4 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with localization and functional readouts, single lab\",\n      \"pmids\": [\"30287900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KGF-1 accelerates wound contraction through a double-paracrine mechanism: KGF-1 stimulates keratinocytes to produce TGF-β1, which then activates fibroblasts; this leads to increased Col-I, p-Smad2, p-Smad3, and α-SMA expression. TGF-β1-neutralizing antibody attenuated the KGF-1-induced contractile capacity of fibroblast-populated collagen lattices.\",\n      \"method\": \"Keratinocyte-fibroblast co-culture, ELISA for TGF-β1, fibroblast-populated collagen lattice contraction assay, TGF-β1 neutralizing antibody, Western blot for Smad pathway components, diabetic rat wound model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection with neutralizing antibody + in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"30894415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FGF7 structural subfamily analysis: members of the FGF7 subfamily (FGF3, FGF7, FGF10, FGF22) achieve restricted specificity for FGFR1b/FGFR2b by engaging specific contacts with two alternatively spliced loop regions in the immunoglobulin-like domain 3 (D3) of these receptors; weak basal receptor-binding affinity further constrains specificity; heparin sulfate co-receptor affinity differences among the four members contribute to their disparate biological activities.\",\n      \"method\": \"Structural analysis review (compilation of crystal structures and mutagenesis data from the field)\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — synthesis of structural and mutagenesis data; review article summarizing prior crystallographic/mutagenesis work rather than a single new experiment\",\n      \"pmids\": [\"30809251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF7 promotes osteoblast dendrite elongation and functional gap junction formation by increasing E11 expression; E11 directly interacted with Cx43 in primary osteoblasts; MAPK and PI3K-AKT pathways were involved in FGF7-mediated E11 upregulation and cell process formation.\",\n      \"method\": \"Co-immunoprecipitation (E11-Cx43 interaction), Western blot, immunofluorescence, pathway inhibitors (MAPK, PI3K-AKT), osteoblast morphology analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction (Co-IP) plus pathway inhibition and functional readout, single lab\",\n      \"pmids\": [\"34671204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FGF7/FGFR2 signaling abolishes progesterone receptor (PR)-mediated modulation of estrogen receptor (ER) activity in luminal breast cancer; FGF7/FGFR2 signaling regulated ER and PR expression and activity, increased ER-PR complex formation, reversed P4-triggered ER-dependent gene deregulation, and required JunB as a prerequisite for abrogating P4-induced growth inhibition.\",\n      \"method\": \"3D cell growth assays, hormone receptor expression and activity assays (ER/PR), ER-PR co-immunoprecipitation, gene expression analysis, JunB functional requirement assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for ER-PR complexes, functional 3D growth assays, molecular pathway analysis, single lab\",\n      \"pmids\": [\"35726195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX9, activated by WNT3A via TCF7, enhances FGF7 transcription and expression in cholangiocarcinoma; secreted FGF7 activates FGFR2 phosphorylation in an autocrine pathway promoting CCA proliferation and pemigatinib resistance.\",\n      \"method\": \"mRNA sequencing, in vitro/in vivo validation, WNT3A stimulation, SOX9 overexpression/knockdown, FGFR2 phosphorylation assay, autocrine secretion measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss of function with signaling readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"35428876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fibro-adipogenic progenitors (FAPs) interact with muscle satellite cells (MuSCs) via FGF7-FGFR2 signaling to promote MuSC proliferation; FGFR2 knockdown in MuSCs abolished the pro-proliferative effects of exogenous FGF7; FGF7 administration increased satellite cell proliferation and enhanced muscle regeneration in injury and aging models.\",\n      \"method\": \"Single-cell RNA sequencing, CellChat cell-cell communication analysis, FGFR2 knockdown, EdU proliferation assays, cardiotoxin injury model, d-galactose aging model, in vivo muscle function assays\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq for interaction identification, FGFR2 knockdown validates receptor requirement, multiple in vitro and in vivo functional assays\",\n      \"pmids\": [\"38751367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cancer-associated fibroblast-derived FGF7 promotes ovarian cancer progression by inhibiting ubiquitination and degradation of HIF-1α via FGFR2 interaction, activating the FGF7/HIF-1α/EMT axis; neutralizing antibodies against FGF7 substantially reduced tumor growth in vivo.\",\n      \"method\": \"In vitro invasion/migration/proliferation assays, single-cell transcriptomic analysis, HIF-1α ubiquitination assay, FGFR2 interaction studies, in vivo neutralizing antibody treatment\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic assay (HIF-1α ubiquitination) plus in vivo antibody neutralization, single lab\",\n      \"pmids\": [\"38491511\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGF7 (KGF) is a mesenchyme-derived, heparin-binding growth factor that signals exclusively through FGFR2 IIIb (KGFR) on epithelial cells, with dermatan sulfate serving as the principal physiological co-receptor in skin; upon receptor activation FGF7 engages Ras-MAPK (ERK1/2), PI3K-Akt, and JNK pathways in a context-dependent manner to drive epithelial proliferation, survival (via Akt), differentiation (via JNK/c-Jun in alveolar cells, SREBP-1 in lipogenesis, β-catenin in bone), and migration (via Grb2-ERK1/2 and integrin α5 upregulation through C/EBP-β); it acts as a presynaptic organizer for inhibitory synapses in neurons (transported by KIF5/gephyrin to inhibitory postsynaptic sites), promotes wound contraction through a double-paracrine TGF-β1/Smad cascade, and can stimulate an autocrine FGF7-FGFR2 loop in certain cancers that activates MAPK, PI3K/Akt/mTOR, and HIF-1α to drive invasion and therapy resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGF7 (KGF) is a secreted, heparin-binding growth factor that drives epithelial proliferation, survival, differentiation, and migration by signaling through a single high-affinity receptor, FGFR2 IIIb (KGFR), engaged with exquisite specificity through residues in its β4/β5 loop and contacts with the alternatively spliced D3 region of the receptor [#0, #14, #29]. This receptor selectivity restricts FGF7's action to epithelia, and its activity additionally depends on a glycosaminoglycan co-receptor: in skin, dermatan sulfate rather than heparan sulfate is the principal physiological cofactor enabling FGF7-dependent receptor binding and signaling [#11, #2]. Receptor engagement is read out through several context-dependent intracellular cascades — Ras-MAPK/ERK1/2 for proliferation and motility [#6, #13, #15], PI3K-Akt(-S6K) for epithelial survival and differentiation [#10, #12, #15], and JNK for maintenance of alveolar type II cell identity [#19] — with these arms feeding distinct transcriptional effectors (SREBP-1 for lipogenesis, C/EBP-β for integrin α5, β-catenin in osteocytes) [#16, #20, #27]. At the tissue level, FGF7-FGFR2 IIIb signaling is required for epidermal morphogenesis and wound reepithelialization [#1], directs surface-ectoderm cell fate including apical ectodermal ridge induction and epidermal-versus-follicle choice [#7, #21], and orchestrates fibrosis and wound contraction through double-paracrine loops in which FGF7 stimulates keratinocytes to secrete OSM or TGF-β1 that then activate fibroblasts [#22, #28]. Beyond epithelia, FGF7 acts as a presynaptic organizer of inhibitory synapses, being transported by KIF5/gephyrin to inhibitory postsynaptic sites [#24], and as a stromal mediator of regeneration that drives muscle satellite-cell proliferation [#33]. In cancer, autocrine and stromal FGF7-FGFR2 loops promote invasion, EMT, and therapy resistance via MMP/uPA induction, PI3K/Akt/mTOR-THBS1, and HIF-1α stabilization [#8, #26, #32, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that KGF/FGF7 acts through its own dedicated high-affinity tyrosine kinase receptor distinct from the bFGF receptor, defining the ligand-receptor axis that all later mechanism rests on.\",\n      \"evidence\": \"Expression cDNA cloning and ligand-binding competition with transformation assay in NIH/3T3 fibroblasts\",\n      \"pmids\": [\"1846048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which epithelial cell types depend on this receptor in vivo\", \"Structural basis of specificity not yet resolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrated that KGFR signaling in basal keratinocytes is physiologically required for epidermal morphogenesis and wound reepithelialization, moving FGF7 from a biochemical activity to an in vivo tissue function.\",\n      \"evidence\": \"Dominant-negative KGFR transgene in mouse keratinocytes with skin histology and wound-healing assays\",\n      \"pmids\": [\"7973639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant-negative blocks all FGFR2 IIIb ligands, not FGF7 specifically\", \"Downstream signaling not dissected\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed that cell-surface heparan sulfate modulates rather than universally promotes FGF7 binding, raising the question of which glycosaminoglycan is the true physiological co-receptor.\",\n      \"evidence\": \"Radioligand binding with chlorate/heparinase treatment in KGFR-expressing cell lines\",\n      \"pmids\": [\"7528211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the physiological co-receptor not resolved here\", \"Low-affinity binding site left unidentified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified dermatan sulfate as the principal skin glycosaminoglycan cofactor enabling FGF7-dependent receptor binding and signaling, resolving the co-receptor question for wounds.\",\n      \"evidence\": \"GAG-panel reconstitution with radiolabeled FGF7 binding, MAPK phosphorylation, and proliferation in BaF/KGFR cells and keratinocytes\",\n      \"pmids\": [\"12215437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dermatan sulfate serves as co-receptor in non-skin tissues unknown\", \"Structural geometry of the FGF7-dermatan-receptor complex not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the structural basis for FGF7's exclusive FGFR2 IIIb specificity by mapping ligand residues that contact the exon-IIIb region, explaining receptor selectivity at atomic resolution.\",\n      \"evidence\": \"Structure-based mutagenesis of FGF7 with receptor binding-affinity and activity assays\",\n      \"pmids\": [\"14527678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental co-crystal structure reported in this entry\", \"Contribution of GAG to specificity addressed only later\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Dissected the downstream signaling logic, showing FGF7 activates ERK-MAPK, PI3K-Akt/S6K, and JNK arms that are deployed differentially for proliferation, survival, and differentiation in distinct epithelia.\",\n      \"evidence\": \"Pharmacological and genetic pathway dissection (wortmannin, rapamycin, PD98059, dominant-negative Akt, JNKK2) with proliferation/survival/differentiation readouts across corneal, pancreatic, alveolar, and breast cells\",\n      \"pmids\": [\"11446769\", \"12732722\", \"15672868\", \"19266047\", \"17872496\", \"9660480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines pathway selection in a given cell type remains unclear\", \"Receptor-proximal adapter usage (Shc/Grb2/Sos) appears context-dependent and incompletely resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected FGF7 signaling arms to specific transcription-factor effectors, showing PI3K/JNK→SREBP-1 drives lipogenic gene expression and ERK→C/EBP-β drives integrin α5, defining transcriptional outputs.\",\n      \"evidence\": \"Promoter reporter mutagenesis, dominant-negative SREBP-1/C/EBP-β, and siRNA in pulmonary and keratinocyte models\",\n      \"pmids\": [\"16162944\", \"20\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector usage may be cell-type restricted\", \"Integration of multiple transcription factors not modeled\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Established FGF7's role in surface-ectoderm fate decisions, including apical ectodermal ridge induction and cell-fate reprogramming, distinguishing it functionally from other FGF family members.\",\n      \"evidence\": \"Chick bead implantation/ectoderm explants with Fgf8 in situ and lens-specific KGF transgenic mice\",\n      \"pmids\": [\"10373311\", \"10525187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mediators of fate change not fully defined\", \"Relationship to FGFR2 IIIb signaling arms not dissected here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed signaling kinetics as a determinant of morphogenetic outcome — transient FGF7-driven ERK promotes growth without branching and dominates over branching-inducing TGFα signals.\",\n      \"evidence\": \"Ex vivo mammary explant culture with ERK time-course and morphological/molecular readouts\",\n      \"pmids\": [\"17448457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism setting ERK duration not identified\", \"Generalizability to other branched epithelia untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified FGF7 as a presynaptic organizer of inhibitory synapses delivered to postsynaptic sites by motor/adaptor machinery, extending FGF7 function beyond epithelia into neurons.\",\n      \"evidence\": \"Live imaging and KIF5/gephyrin knockdown in hippocampal neurons with synapse-targeting assays\",\n      \"pmids\": [\"25431136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating the synaptic-organizing activity not defined here\", \"In vivo significance for inhibitory circuits untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined double-paracrine epithelial-mesenchymal loops (KGF→keratinocyte→OSM/TGF-β1→fibroblast) as the mechanism for FGF7-driven fibrosis and wound contraction.\",\n      \"evidence\": \"Conditioned-medium experiments, neutralizing antibodies, STAT3/Smad signaling readouts, and collagen-lattice contraction with in vivo wound models\",\n      \"pmids\": [\"23096718\", \"30894415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanisms\", \"Relative contributions of OSM versus TGF-β1 loops in different contexts unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed FGF7 downstream of GLP-1 receptor signaling as a required mediator of intestinal mucosal growth, linking it into a systemic hormone-growth axis via genetic epistasis.\",\n      \"evidence\": \"Fgf7-knockout mice with exendin-4 treatment and overlapping gene-expression analysis in Apc(Min/+) models\",\n      \"pmids\": [\"25738454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source and target of Fgf7 in this axis not fully defined\", \"Receptor-level mechanism not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established autocrine and stromal FGF7-FGFR2 loops as drivers of cancer invasion, EMT, hormone-receptor crosstalk, and targeted-therapy resistance across multiple tumor types.\",\n      \"evidence\": \"FGFR2/THBS1 knockdown, HIF-1α ubiquitination assays, ER-PR co-IP, SOX9/WNT3A manipulation, and in vivo neutralizing antibodies in gastric, ovarian, breast, and cholangiocarcinoma models\",\n      \"pmids\": [\"28339036\", \"38491511\", \"35726195\", \"35428876\", \"10389758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each cancer mechanism shown in a single lab\", \"Whether the same pathway operates across tumor types not cross-validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended FGF7-FGFR2 signaling to regenerative niche communication, with fibro-adipogenic progenitor-derived FGF7 driving muscle satellite-cell proliferation and regeneration.\",\n      \"evidence\": \"scRNA-seq/CellChat interaction analysis, FGFR2 knockdown, EdU assays, and injury/aging mouse models\",\n      \"pmids\": [\"38751367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular pathway in satellite cells not fully mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ligand-receptor pair selects among ERK, Akt, and JNK arms to produce opposing outcomes (proliferation vs. differentiation vs. survival) in different cell types remains the central unresolved mechanistic question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking co-receptor identity, signaling kinetics, and effector selection\", \"Structural co-crystal of the FGF7-FGFR2 IIIb-GAG ternary complex not reported in the corpus\", \"Receptor for neuronal/synaptic FGF7 activity unconfirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 14, 29]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0008201\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [28, 32, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 13, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 7, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 26, 32, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGFR2\", \"KIF5\", \"GPHN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}