{"gene":"FGF7","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1989,"finding":"KGF (FGF7) is a stromal cell-derived mitogen specific for epithelial cells, identified as a member of the FGF family by cDNA sequencing, with expression restricted to stromal cells of epithelial tissues.","method":"cDNA cloning, expression analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — original cloning with functional characterization, foundational paper with 958 citations","pmids":["2475908"],"is_preprint":false},{"year":1991,"finding":"KGF receptor was identified as a transmembrane tyrosine kinase (FGFR2 IIIb) distinct from the basic FGF receptor, with high affinity for KGF and acidic FGF, cloned by an autocrine transformation assay in NIH/3T3 cells.","method":"Expression cDNA library cloning, receptor binding competition assay, transformation focus assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — functional receptor cloning with binding and signaling validation, foundational paper with 442 citations","pmids":["1846048"],"is_preprint":false},{"year":1994,"finding":"KGF receptor signaling is required for normal epidermal morphogenesis and wound reepithelialization; dominant-negative KGF receptor transgene in basal keratinocytes caused epidermal atrophy, hair follicle abnormalities, and substantially delayed wound reepithelialization with reduced keratinocyte proliferation at the wound edge.","method":"Dominant-negative transgenic mouse model, histology, proliferation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function transgenic with defined cellular phenotype, 504 citations","pmids":["7973639"],"is_preprint":false},{"year":2002,"finding":"Dermatan sulfate (chondroitin sulfate B), the predominant glycosaminoglycan in skin, acts as the principal co-factor for FGF7 activity; it enables FGF7-dependent FGFR2 IIIb binding, MAPK phosphorylation, and keratinocyte proliferation, whereas heparan sulfate and chondroitin sulfate A/C do not support FGF7 activity.","method":"Cell proliferation assay (BaF/KGFR lymphoid cell line), radiolabeled FGF7 receptor binding assay, MAPK phosphorylation assay, glycosaminoglycan fractionation","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal assays in a single rigorous study","pmids":["12215437"],"is_preprint":false},{"year":2003,"finding":"Structure-based mutagenesis identified specific FGF7 residues (β4/β5 loop, Asp63, Leu142, Arg65) required for exclusive binding to FGFR2IIIb; mutations in these residues reduced receptor binding affinity and biological activity.","method":"Structure-based modeling, site-directed mutagenesis, receptor binding assay, biological activity assay","journal":"FEBS Letters","confidence":"High","confidence_rationale":"Tier 1 — structure-guided mutagenesis with functional validation of binding specificity","pmids":["14527678"],"is_preprint":false},{"year":2019,"finding":"Structural analysis reveals that FGF7 subfamily members (FGF3, FGF7, FGF10, FGF22) achieve restricted specificity for FGFR1b/FGFR2b by engaging alternatively spliced loop regions in the immunoglobulin-like domain 3 (D3) of these receptors, with weak basal receptor-binding affinity further constraining specificity.","method":"Structural analysis, comparative receptor-binding analysis","journal":"Frontiers in Genetics","confidence":"Medium","confidence_rationale":"Tier 1 review of structural data — strong structural basis but review article compiling existing structural evidence","pmids":["30809251"],"is_preprint":false},{"year":2005,"finding":"FGF-binding protein (FGF-BP) physically interacts with FGF7, FGF10, and FGF22, and enhances the biological activity of low concentrations of these ligands; FGF-BP expression is upregulated after skin injury in keratinocytes.","method":"Co-immunoprecipitation/pulldown binding assay, in vitro activity assay, wound model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — binding demonstrated with functional enhancement, single lab study","pmids":["15806171"],"is_preprint":false},{"year":2003,"finding":"KGF (FGF7) inducible expression in mouse lung activates the Akt pro-survival signaling axis in lung epithelial cells (not endothelial cells), and dominant-negative Akt blocks KGF-mediated protection from hyperoxia-induced cell death, consistent with selective KGFR expression on epithelium.","method":"Tetracycline-inducible transgenic mouse system, dominant-negative Akt mutant, in vitro and in vivo cell death assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic system with mechanistic epistasis via dominant-negative, multiple orthogonal methods","pmids":["12732722"],"is_preprint":false},{"year":2007,"finding":"KGF signaling in thymic epithelial cells activates the p53 and NF-κB pathways and induces transcription of BMP2, BMP4, Wnt5b, and Wnt10b; canonical BMP signaling is critical for KGF-mediated TEC expansion and T-cell development.","method":"In vivo KGF administration, signaling pathway analysis, pathway inhibition experiments, gene expression profiling","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mechanistic follow-up with pathway inhibition, single lab","pmids":["17213286"],"is_preprint":false},{"year":2005,"finding":"KGF/FGF7 induces lipogenesis in pulmonary epithelial H292 cells through a PI3K and JNK/SREBP-1 signaling pathway; KGF activates Akt, p70 S6K, JNK, and ERK; JNK and PI3K (but not ERK) are required for SREBP-1, FAS, and SCD-1 induction; SREBP-1 binding site in SCD-1 promoter is required for KGF effect.","method":"Pharmacological pathway inhibition (SP600125, LY294002, PD98059), luciferase promoter assays, dominant-negative and dominant-active SREBP-1 adenoviral constructs, Western blot","journal":"Journal of Lipid Research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including promoter mutagenesis and dominant constructs in a single study","pmids":["16162944"],"is_preprint":false},{"year":2009,"finding":"KGF promotes ductal cell proliferation through the MEK-ERK1/2 pathway and ductal cell differentiation (PDX1, Glut2 expression) through a PI3K/AKT-dependent mechanism in pancreatic duct cells, contributing to beta-cell neogenesis.","method":"BrdU incorporation assay, pharmacological MEK inhibition (in vitro and in vivo), morpholino antisense against MEK1, PI3K inhibition, immunolocalization","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic epistasis with defined cellular readouts, in vitro and in vivo","pmids":["19266047"],"is_preprint":false},{"year":2007,"finding":"KGF-induced retention of alveolar type II cell phenotype (preventing transdifferentiation to type I-like cells) is mediated specifically by JNK activation and downstream c-Jun phosphorylation; inhibition of JNK (but not ERK1/2 or p38) abrogates this effect, and overexpression of JNKK2 promotes AT2 phenotype markers.","method":"Primary rat AEC culture, selective MAPK inhibitors, JNKK2 overexpression, immunoblot, monoclonal antibody phenotyping","journal":"American Journal of Respiratory Cell and Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic epistasis with clean phenotypic readout","pmids":["17872496"],"is_preprint":false},{"year":1997,"finding":"KGF protects airway epithelial cells against H2O2-induced permeability increase and disruption of F-actin cytoskeleton via a PKC-dependent mechanism; calphostin C (PKC inhibitor) abolishes both the KGF-mediated decrease in basal albumin flux and protection against H2O2.","method":"Transwell permeability assay, pharmacological PKC inhibition, F-actin immunostaining","journal":"American Journal of Physiology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with defined functional readout and cytoskeletal mechanism","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 (blocked by aphidicolin and butylphenyl dGTP but not dideoxythymidine triphosphate, ruling out polymerase-β).","method":"Alkaline unwinding DNA damage assay, selective DNA polymerase inhibitors","journal":"American Journal of Physiology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with multiple inhibitors defining the DNA repair mechanism","pmids":["9227520"],"is_preprint":false},{"year":1998,"finding":"KGF upregulates active Na+ transport across alveolar epithelial cell monolayers by increasing Na+/K+-ATPase α1 subunit mRNA and protein (α1 and β1 subunit protein), without increasing rENaC subunit mRNAs (which actually decrease), suggesting Na pump upregulation as the primary mechanism.","method":"Short-circuit current measurement, quantitative mRNA assay, Western blot","journal":"American Journal of Physiology","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss/gain-of-function with defined molecular and functional readouts","pmids":["9458813"],"is_preprint":false},{"year":2009,"finding":"KGF promotes limbal epithelial outgrowth by inducing ΔNp63α expression through the p38 MAPK pathway; inhibition of p38 blocks KGF-induced ΔNp63α upregulation, and knockdown of ΔNp63α significantly reduces KGF-induced outgrowth.","method":"Ex vivo limbal explant culture, kinase inhibitor studies, siRNA knockdown, immunofluorescence","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic epistasis with defined downstream transcription factor","pmids":["19920075"],"is_preprint":false},{"year":2006,"finding":"KGF suppresses α2β1 integrin expression and function in prostatic epithelial transient amplifying population (TAP) cells, inducing differentiation (PAP, CK18, androgen receptor expression) via p38-MAPK; p38 inhibitor (SB202190) blocks KGF-induced differentiation.","method":"Primary human prostate epithelial culture, flow cytometry, immunofluorescence, pharmacological p38 inhibition, FGFR2 expression analysis by FACS","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with defined differentiation phenotype in primary human cells","pmids":["16554439"],"is_preprint":false},{"year":2014,"finding":"FGF7/KGF induces autophagy in human keratinocytes via a PI3K-AKT-MTOR-independent pathway, stimulating autophagosome formation; upon prolonged stimulus, FGF7 also accelerates autophagosome turnover. Autophagy is required for FGF7-mediated early differentiation (KRT1/K1 upregulation), as shown by 3-MA, BECN1, and ATG5 depletion.","method":"Quantitative fluorescence assays of autophagy, selective autophagy inhibitors (3-MA, bafilomycin A1), siRNA knockdown of BECN1 and ATG5, Western blot","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic knockdown and pharmacological inhibition with functional readout","pmids":["24577098"],"is_preprint":false},{"year":2014,"finding":"FGF7 localizes to inhibitory postsynaptic sites in hippocampal neurons and functions as a presynaptic organizer for inhibitory (but not excitatory) synapse differentiation; its selective inhibitory synaptic targeting requires the motor protein KIF5 and the adaptor protein gephyrin for microtubule transport, with FGF7 co-transported with gephyrin as shown by time-lapse imaging.","method":"Time-lapse live imaging, co-localization assays, dominant-negative motor protein experiments, immunofluorescence, siRNA knockdown","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — direct live imaging of transport, motor protein epistasis, established synaptic function with specific molecular machinery","pmids":["25431136"],"is_preprint":false},{"year":2012,"finding":"Increased KGF expression induces fibroblast activation through a double paracrine loop: KGF stimulates keratinocytes to produce and secrete oncostatin M (OSM), which then activates fibroblasts (collagen I-α1 upregulation, increased migration) via OSM-regulated STAT3 phosphorylation and urokinase plasminogen activator expression.","method":"Co-culture systems, ELISA, Western blot (STAT3 phosphorylation), siRNA knockdown, migration assays","journal":"Journal of Investigative Dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — paracrine loop mechanistically dissected with molecular readouts, single lab","pmids":["23096718"],"is_preprint":false},{"year":2019,"finding":"KGF-1 promotes wound contraction via a double-paracrine mechanism: KGF-1 stimulates keratinocytes to secrete TGF-β1, which then activates fibroblasts to contract collagen lattices; TGF-β1 neutralizing antibody attenuates KGF-1-induced fibroblast contraction, and this involves the TGF-β1/Smad2/3 pathway with α-SMA and collagen I upregulation.","method":"Keratinocyte-fibroblast co-culture, fibroblast-populated collagen lattice (FPCL) contraction assay, ELISA (TGF-β1), Western blot (p-Smad2/3, α-SMA, Col-I), TGF-β1 neutralizing antibody, diabetic rat wound model","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, neutralizing antibody epistasis, in vitro and in vivo validation","pmids":["30894415"],"is_preprint":false},{"year":2007,"finding":"KGF-induced motility of breast cancer cells requires Grb2 (an adaptor protein) and ERK1/2 activation downstream of the KGF receptor tyrosine kinase; Grb2 knockdown and ERK1/2 inhibition (PD98059) suppress KGF-induced motility, whereas Akt inhibition (wortmannin) does not.","method":"Antisense/siRNA knockdown of Grb2, pharmacological ERK and Akt inhibition, wounding motility assay, cDNA microarray","journal":"Clinical & Experimental Metastasis","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown plus pharmacological epistasis with defined functional readout","pmids":["15672868"],"is_preprint":false},{"year":2000,"finding":"IL-1α produced by prostatic epithelial cells acts as a paracrine inducer of FGF7 expression in prostatic stromal cells; blocking with anti-IL-1α antibodies or IL-1Ra abrogates the epithelial conditioned medium-induced FGF7 upregulation in stroma, establishing a double paracrine loop.","method":"Conditioned medium experiments, neutralizing antibody blocking, ELISA, immunohistochemistry","journal":"American Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 — neutralizing antibody epistasis with molecular readout identifying the upstream inducer of FGF7","pmids":["10880394"],"is_preprint":false},{"year":1996,"finding":"KGF can replace testosterone as a paracrine mediator of ductal branching morphogenesis in rat ventral prostate; KGF is expressed in prostatic mesenchyme and its receptor exclusively in epithelium; neutralization of endogenous KGF with anti-KGF antibody or soluble KGFR inhibits androgen-stimulated growth and reduces ductal end buds.","method":"RT-PCR expression analysis, in situ hybridization, organ culture with neutralizing antibody and soluble receptor peptide, DNA content assay","journal":"International Journal of Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor localization plus loss-of-function with neutralizing antibody and soluble receptor, defined morphological readout","pmids":["8946242"],"is_preprint":false},{"year":2015,"finding":"GLP-1 receptor signaling promotes intestinal mucosal growth through FGF7; exendin-4 increases Fgf7 expression, and intestinal growth response to exendin-4 is absent in Fgf7-/- mice, placing FGF7 downstream of GLP-1R in intestinal mucosal expansion.","method":"Glp1r-/- and Fgf7-/- mouse genetic epistasis, exendin-4 treatment, gene expression analysis, intestinal morphometry","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis with two knockout models and defined pathway position","pmids":["25738454"],"is_preprint":false},{"year":2017,"finding":"FGF7/FGFR2 signaling promotes invasion and migration of gastric cancer cells through upregulation of THBS1 (thrombospondin-1) via the PI3K/Akt/mTOR pathway; FGFR2 or THBS1 knockdown suppresses FGF7-induced invasion/migration.","method":"siRNA knockdown of FGFR2 and THBS1, invasion/migration assays, PI3K/Akt/mTOR pathway inhibitor studies, Western blot","journal":"International Journal of Oncology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown with pharmacological epistasis and defined invasion readout","pmids":["28339036"],"is_preprint":false},{"year":2018,"finding":"FGF7 promotes osteocyte cell processes by inducing β-catenin cytoplasmic accumulation and nuclear translocation, which increases connexin43 (Cx43) expression and gap junction formation between osteocytes.","method":"Western blot, immunofluorescence (β-catenin nuclear translocation), gap junction/cell process assays in MLO-Y4 cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway established with β-catenin localization and Cx43 functional readout, single lab","pmids":["30287900"],"is_preprint":false},{"year":2021,"finding":"FGF7 promotes osteoblast dendrite elongation and gap junctional intercellular communication (GJIC) by inducing E11 expression; E11 directly interacts with connexin43 (Cx43) in primary osteoblasts; MAPK and PI3K-AKT pathways are involved.","method":"Western blot, immunofluorescence, co-immunoprecipitation (E11-Cx43 interaction), GJIC functional assay, pathway inhibition","journal":"International Journal of Biological Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP for E11-Cx43 interaction plus pathway inhibition and functional GJIC readout","pmids":["34671204"],"is_preprint":false},{"year":2024,"finding":"Fibro-adipogenic progenitors (FAPs) signal to muscle satellite cells (MuSCs) via FGF7-FGFR2; exogenous FGF7 promotes MuSC proliferation and muscle regeneration, and FGFR2 knockdown abolishes FGF7-induced proliferation.","method":"Single-cell RNA sequencing, CellChat ligand-receptor analysis, EdU proliferation assay, FGFR2 siRNA knockdown, cardiotoxin injury and d-galactose aging models in vivo","journal":"Journal of Cachexia, Sarcopenia and Muscle","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq cell communication validated by receptor knockdown and in vivo functional assays","pmids":["38751367"],"is_preprint":false},{"year":2022,"finding":"SOX9, induced by WNT3A-TCF7 signaling, transcriptionally upregulates both FGF7 and FGFR2 in cholangiocarcinoma; FGF7 is secreted and activates FGFR2 in an autocrine pathway, promoting CCA proliferation and pemigatinib resistance; neutralizing FGF7 or inhibiting HIF-1α reverses FGF7-mediated EMT.","method":"mRNA sequencing, in vitro/in vivo validation, WNT3A stimulation assays, FGF7 neutralizing antibody, HIF-1α pathway inhibition","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway from Wnt to FGF7 autocrine loop with neutralizing antibody functional validation","pmids":["35428876"],"is_preprint":false},{"year":2021,"finding":"FGF7-FGFR2 autocrine signaling in fusion-gene-positive (PAX3-FOXO1) rhabdomyosarcoma sustains MAPK activity and promotes cell viability and chemoresistance; genetic silencing of FGFR2 or FGF7 decreases cell viability, and pharmacological FGFR inhibition reduces tumor growth in vivo.","method":"siRNA knockdown of FGFR2 and FGF7, MAPK activity assay, FGFR inhibitor (NVP-BGJ398), xenograft tumor model","journal":"Molecular Oncology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis with in vitro and in vivo functional readouts","pmids":["34850536"],"is_preprint":false},{"year":2024,"finding":"CAF-derived FGF7 inhibits ubiquitination and degradation of HIF-1α via FGFR2 interaction in ovarian cancer cells, activating HIF-1α-dependent EMT; neutralizing antibodies against FGF7 substantially reduce tumor growth in vivo.","method":"Single-cell transcriptomic analysis, in vitro FGFR2 binding assays, HIF-1α ubiquitination assay, neutralizing antibody treatment, xenograft model","journal":"Journal of Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway (FGF7/FGFR2/HIF-1α/EMT) supported by multiple in vitro methods and in vivo antibody validation","pmids":["38491511"],"is_preprint":false},{"year":1996,"finding":"The KGF/FGF7 promoter is androgen-regulated; transient transfection in LNCaP cells with the synthetic androgen R1881 upregulated KGF promoter activity 6–11-fold, with androgen-responsive elements mapping to the region -900 to -1200.","method":"Promoter-reporter transfection assay, androgen stimulation","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — promoter-reporter functional assay with defined responsive region, single lab","pmids":["8607856"],"is_preprint":false},{"year":2007,"finding":"KGF promotes integrin α5 expression in keratinocytes by inducing sustained ERK1/2-dependent phosphorylation of C/EBP-β transcription factor; dominant-negative C/EBP-β inhibits α5 promoter activity and C/EBP-β siRNA reduces integrin α5 expression.","method":"Promoter-reporter assay, dominant-negative C/EBP-β, siRNA knockdown, Western blot (ERK1/2, C/EBP-β phosphorylation), 3D epidermal tissue analogues","journal":"American Journal of Physiology - Cell Physiology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter-reporter with genetic epistasis (DN construct and siRNA), multiple orthogonal approaches","pmids":["17596295"],"is_preprint":false},{"year":1999,"finding":"In salivary gland branching morphogenesis, FGF7 and EGF produce distinct morphological outcomes: EGF induces lobule formation and cleft formation, while FGF7 promotes stalk elongation associated with differential cell proliferation (higher in distal regions); these effects correlate with spatially distinct patterns of FGFR expression.","method":"Mesenchyme-free salivary epithelial explant culture, BrdU labeling, whole-mount analysis","journal":"Developmental Dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — defined morphological phenotypes with BrdU proliferation mapping in functional organ culture","pmids":["10373019"],"is_preprint":false},{"year":2003,"finding":"AS101-induced hair growth is mediated by KGF; anti-KGF neutralizing antibodies and dominant-negative KGF receptor transgene abolish the AS101-induced anagen; AS101 upregulates KGF expression in fibroblasts via the Ras signaling pathway.","method":"Neutralizing antibody, dominant-negative transgenic mouse, fibroblast culture with Ras pathway analysis","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 — antibody and genetic epistasis placing KGF downstream of Ras in hair growth induction","pmids":["14656992"],"is_preprint":false}],"current_model":"FGF7 (KGF) is a mesenchyme-derived, heparin-binding growth factor that acts exclusively through FGFR2 IIIb (the KGF receptor) on epithelial cells, using dermatan sulfate as its principal co-receptor in skin; its β4/β5 loop and specific residues (Asp63, Leu142, Arg65) confer exclusive FGFR2IIIb binding specificity; downstream signaling activates PI3K/Akt, ERK1/2, JNK, and p38 MAPK in a context-dependent manner to drive epithelial proliferation, differentiation, survival, autophagy, and cytoskeletal reorganization; in the nervous system FGF7 localizes to inhibitory postsynaptic sites via KIF5/gephyrin-mediated transport to organize inhibitory presynaptic differentiation; and in various tissues it operates through double paracrine loops (e.g., with TGF-β1 and IL-1α) and autocrine FGFR2 signaling to regulate organ morphogenesis, wound healing, thymic regeneration, and tumor progression."},"narrative":{"teleology":[{"year":1989,"claim":"The identity of a stromal-derived epithelial mitogen was unknown; cloning FGF7/KGF from fibroblast-conditioned medium established it as a novel FGF family member with expression restricted to stromal cells of epithelial tissues, defining the mesenchymal-to-epithelial paracrine paradigm.","evidence":"cDNA cloning and expression analysis from human fibroblast-conditioned medium","pmids":["2475908"],"confidence":"High","gaps":["No receptor identified","Downstream signaling unknown","In vivo function not established"]},{"year":1991,"claim":"The receptor mediating KGF's epithelial specificity was unknown; identification of FGFR2 IIIb as the KGF receptor explained why KGF acts exclusively on epithelial cells that express this splice variant.","evidence":"Expression cDNA library screen with autocrine transformation assay in NIH/3T3 cells, receptor binding competition","pmids":["1846048"],"confidence":"High","gaps":["Structural basis for receptor selectivity unknown","Co-receptor requirements not defined","In vivo requirement not tested"]},{"year":1994,"claim":"Whether KGF receptor signaling was required for epithelial homeostasis in vivo was untested; dominant-negative KGFR in transgenic mice demonstrated that this pathway is essential for normal epidermal morphogenesis, hair follicle development, and wound reepithelialization.","evidence":"Dominant-negative KGFR transgenic mouse, histology and proliferation assays at wound edges","pmids":["7973639"],"confidence":"High","gaps":["Downstream signaling pathways not dissected","Relative contribution of FGF7 versus other FGFR2b ligands (FGF10, FGF22) not resolved"]},{"year":1996,"claim":"The role of FGF7 in organ morphogenesis beyond skin was unclear; work in prostate organ culture showed FGF7 mediates androgen-driven ductal branching morphogenesis via mesenchyme-epithelium paracrine signaling, and its promoter contains androgen-responsive elements.","evidence":"Prostate organ culture with anti-KGF neutralizing antibody and soluble KGFR; promoter-reporter assays with androgen stimulation in LNCaP cells","pmids":["8946242","8607856"],"confidence":"Medium","gaps":["Androgen-responsive element identity not fully mapped","Whether other FGFs compensate in vivo unknown"]},{"year":1997,"claim":"The cytoprotective mechanisms downstream of KGF were undefined; studies in airway epithelial cells revealed PKC-dependent barrier protection and F-actin stabilization, and enhanced DNA repair capacity through replicative DNA polymerases α, δ, and ε.","evidence":"Transwell permeability with PKC inhibitors; alkaline unwinding DNA damage assay with selective polymerase inhibitors in pulmonary epithelial cells","pmids":["9142942","9227520"],"confidence":"Medium","gaps":["Direct PKC isoform not identified","Connection between DNA repair induction and receptor signaling cascades not mapped"]},{"year":2002,"claim":"The glycosaminoglycan co-receptor for FGF7 was assumed to be heparan sulfate by analogy with other FGFs; dermatan sulfate was identified as the principal co-receptor in skin, uniquely enabling FGFR2 IIIb binding, MAPK activation, and keratinocyte proliferation.","evidence":"Reconstituted receptor binding, MAPK phosphorylation, and proliferation assays with fractionated GAGs in BaF/KGFR cells","pmids":["12215437"],"confidence":"High","gaps":["Structural basis of dermatan sulfate–FGF7 interaction not resolved","Whether other tissues use different co-receptor GAGs unknown"]},{"year":2003,"claim":"The structural determinants of FGF7's exclusive FGFR2b specificity were unknown; structure-based mutagenesis identified the β4/β5 loop and residues Asp63, Leu142, and Arg65 as critical for receptor binding and biological activity.","evidence":"Site-directed mutagenesis guided by structural modeling, receptor binding and activity assays","pmids":["14527678"],"confidence":"High","gaps":["No co-crystal structure of FGF7–FGFR2b complex at that time","Contribution of each residue to affinity versus specificity not fully deconvolved"]},{"year":2003,"claim":"How KGF protects epithelial cells from oxidative death was mechanistically undefined; inducible KGF expression in mouse lung demonstrated PI3K/Akt activation selectively in epithelial cells, and dominant-negative Akt blocked KGF-mediated protection from hyperoxia.","evidence":"Tetracycline-inducible KGF transgenic mice, dominant-negative Akt, in vivo and in vitro cell death assays","pmids":["12732722"],"confidence":"High","gaps":["Downstream Akt substrates mediating survival not identified","Whether Akt is required for all KGF cytoprotective effects unknown"]},{"year":2005,"claim":"Context-dependent divergence of MAPK branches downstream of KGF was unresolved; JNK and PI3K (but not ERK) were shown to drive KGF-induced lipogenesis via SREBP-1 in pulmonary epithelial cells, while ERK drove proliferation and motility in other contexts.","evidence":"Pharmacological inhibitors, dominant-negative/active SREBP-1 constructs, promoter mutagenesis in H292 cells; Grb2 knockdown and ERK inhibition in breast cancer motility assays","pmids":["16162944","15672868"],"confidence":"Medium","gaps":["How the same receptor activates different MAPK branches in different cell types not explained","In vivo relevance of KGF-driven lipogenesis not tested"]},{"year":2007,"claim":"How KGF maintains epithelial cell identity versus driving differentiation through specific MAPK branches was unclear; JNK/c-Jun was shown to maintain alveolar type II cell phenotype, p38 was shown to drive prostatic and limbal epithelial differentiation, and ERK-C/EBPβ controlled integrin α5 expression in keratinocytes.","evidence":"Selective MAPK inhibitors with JNKK2 overexpression in primary rat AECs; p38 inhibitor and siRNA in prostate TAP cells and limbal explants; DN-C/EBPβ and siRNA in keratinocytes","pmids":["17872496","16554439","19920075","17596295"],"confidence":"Medium","gaps":["How pathway selection is determined at the receptor level unknown","Cross-talk between JNK, p38, and ERK branches not dissected"]},{"year":2000,"claim":"Upstream regulators and paracrine feedback circuits controlling FGF7 expression were incompletely defined; IL-1α from prostatic epithelial cells was identified as the paracrine inducer of FGF7 in stromal cells, establishing a double paracrine loop.","evidence":"Conditioned medium with anti-IL-1α neutralizing antibodies and IL-1Ra in prostatic cell co-cultures","pmids":["10880394"],"confidence":"Medium","gaps":["Whether IL-1α–FGF7 loop operates in non-prostatic tissues not tested","Transcription factors mediating IL-1α induction of FGF7 not identified"]},{"year":2012,"claim":"The mechanism by which KGF coordinates epithelial-mesenchymal crosstalk beyond direct epithelial stimulation was unclear; KGF was shown to induce keratinocyte secretion of oncostatin M, which activates fibroblasts via STAT3 to promote collagen and migration — a double paracrine wound-healing circuit.","evidence":"Keratinocyte-fibroblast co-culture, STAT3 phosphorylation, siRNA knockdown, migration assays","pmids":["23096718"],"confidence":"Medium","gaps":["Whether OSM loop operates in vivo during wound healing not confirmed","Other keratinocyte-derived mediators in this circuit not explored"]},{"year":2014,"claim":"Whether FGF7 induces autophagy and how autophagy relates to keratinocyte differentiation was unknown; FGF7 was shown to stimulate mTOR-independent autophagy in keratinocytes, and BECN1/ATG5-dependent autophagy was required for FGF7-induced early differentiation (K1 expression).","evidence":"Autophagy flux assays, 3-MA and bafilomycin A1 treatment, BECN1 and ATG5 siRNA in human keratinocytes","pmids":["24577098"],"confidence":"Medium","gaps":["Upstream signal connecting FGFR2b to autophagy initiation not identified","In vivo relevance of autophagy for FGF7-driven differentiation untested"]},{"year":2014,"claim":"How FGF7 functions outside epithelial tissues was largely unknown; in hippocampal neurons, FGF7 was found to localize selectively to inhibitory postsynaptic sites via KIF5/gephyrin-mediated microtubule transport and to organize inhibitory (not excitatory) presynaptic differentiation.","evidence":"Time-lapse live imaging of FGF7-gephyrin co-transport, dominant-negative motor protein experiments, co-localization, siRNA in hippocampal neurons","pmids":["25431136"],"confidence":"High","gaps":["Whether FGF7 acts through FGFR2b or another receptor at synapses not determined","Mechanism by which FGF7 organizes presynaptic vesicle clustering not elucidated"]},{"year":2015,"claim":"The upstream signals inducing FGF7 in the intestinal niche were unknown; GLP-1 receptor signaling was shown to require FGF7 for intestinal mucosal growth, as Fgf7-/- mice failed to respond to exendin-4.","evidence":"Genetic epistasis with Fgf7-/- and Glp1r-/- mice, exendin-4 treatment, intestinal morphometry","pmids":["25738454"],"confidence":"High","gaps":["Cell type producing FGF7 downstream of GLP-1R not definitively identified","Whether this pathway operates in human intestine not established"]},{"year":2019,"claim":"The mechanism by which KGF drives wound contraction was unclear; KGF was shown to stimulate keratinocyte TGF-β1 secretion, which activates fibroblast contraction via Smad2/3-dependent α-SMA and collagen I upregulation, validated by TGF-β1 neutralizing antibody in vitro and in a diabetic rat wound model.","evidence":"Keratinocyte-fibroblast co-culture, FPCL contraction, TGF-β1 ELISA, neutralizing antibody, diabetic rat wound model","pmids":["30894415"],"confidence":"High","gaps":["Whether this loop is the dominant wound contraction mechanism versus other pathways not established","Diabetic-specific versus general wound context not fully dissected"]},{"year":2021,"claim":"Whether FGF7-FGFR2 autocrine signaling operates in cancer cells (beyond paracrine) and contributes to therapy resistance was unclear; autocrine FGF7-FGFR2 loops were demonstrated in PAX3-FOXO1 rhabdomyosarcoma sustaining MAPK and viability, and in cholangiocarcinoma where SOX9 transcriptionally drives both FGF7 and FGFR2, promoting pemigatinib resistance.","evidence":"siRNA knockdown of FGF7 and FGFR2, FGFR inhibitors, xenograft models; WNT3A-SOX9 axis mapping and FGF7 neutralizing antibody in CCA","pmids":["34850536","35428876"],"confidence":"Medium","gaps":["Whether autocrine FGF7 loops are general features of FGFR2-amplified cancers not determined","Patient-derived validation limited"]},{"year":2024,"claim":"Whether FGF7 plays a paracrine role in muscle regeneration was untested; fibro-adipogenic progenitor-derived FGF7 was shown to promote muscle satellite cell proliferation via FGFR2, with FGFR2 knockdown abolishing the proliferative response.","evidence":"scRNA-seq with CellChat, EdU proliferation, FGFR2 siRNA, cardiotoxin injury and aging models in vivo","pmids":["38751367"],"confidence":"Medium","gaps":["Whether FGF7 or FGF10 is the dominant FGFR2b ligand in muscle regeneration not resolved","Downstream signaling in satellite cells not mapped"]},{"year":null,"claim":"Key unresolved questions include: how the same FGFR2b receptor selectively activates different MAPK branches in different cell types; the structural basis of dermatan sulfate co-receptor function; whether FGF7's neuronal synapse-organizing function acts through FGFR2b; and the full scope of autocrine FGF7-FGFR2 signaling in therapy-resistant cancers.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure of FGF7–dermatan sulfate–FGFR2b ternary complex","Mechanism of context-dependent MAPK branch selection downstream of FGFR2b not resolved","Receptor identity for neuronal FGF7 synapse function not confirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,20,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,19,20,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,9,10,11,15,16,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,23,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[25,29,30,31]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[18]}],"complexes":[],"partners":["FGFR2","KIF5","GPHN","GRB2","FGFBP1","CTNNB1"],"other_free_text":[]},"mechanistic_narrative":"FGF7 (also known as KGF) is a mesenchyme-derived paracrine growth factor that signals exclusively through the epithelial-specific receptor FGFR2 IIIb to drive epithelial proliferation, differentiation, survival, and morphogenesis across diverse tissues including skin, lung, prostate, intestine, and thymus [PMID:2475908, PMID:1846048, PMID:7973639]. Receptor specificity is conferred by FGF7's β4/β5 loop and residues Asp63, Leu142, and Arg65 engaging the alternatively spliced D3 domain of FGFR2b, with dermatan sulfate serving as the principal glycosaminoglycan co-receptor in skin [PMID:14527678, PMID:12215437]. Downstream, FGF7 activates PI3K/Akt, ERK1/2, JNK, and p38 MAPK in a context-dependent manner — ERK drives proliferation and motility, PI3K/Akt mediates survival and differentiation, JNK controls epithelial phenotype maintenance and lipogenesis, and p38 governs progenitor cell differentiation — while also inducing autophagy-dependent keratinocyte differentiation and double paracrine loops (via TGF-β1, OSM, or IL-1α) that coordinate epithelial–mesenchymal crosstalk in wound healing and tissue remodeling [PMID:12732722, PMID:16162944, PMID:17872496, PMID:16554439, PMID:24577098, PMID:30894415, PMID:23096718]. Beyond epithelial tissues, FGF7 functions in hippocampal neurons where it is transported to inhibitory postsynaptic sites via KIF5/gephyrin-mediated microtubule transport to organize inhibitory presynaptic differentiation [PMID:25431136]."},"prefetch_data":{"uniprot":{"accession":"P21781","full_name":"Fibroblast growth factor 7","aliases":["Heparin-binding growth factor 7","HBGF-7","Keratinocyte growth factor"],"length_aa":194,"mass_kda":22.5,"function":"Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation. Required for normal branching morphogenesis. Growth factor active on keratinocytes. 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FGF22","url":"https://www.omim.org/entry/605831"},{"mim_id":"602115","title":"FIBROBLAST GROWTH FACTOR 10; FGF10","url":"https://www.omim.org/entry/602115"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35783154","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":"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":"30155985","id":"PMC_30155985","title":"TGF beta inhibits HGF, FGF7, and FGF10 expression in normal and IPF lung fibroblasts.","date":"2018","source":"Physiological 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17596295","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":"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":"35726195","id":"PMC_35726195","title":"FGF7/FGFR2-JunB signalling counteracts the effect of progesterone in luminal breast cancer.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35726195","citation_count":18,"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":18,"is_preprint":false},{"pmid":"10873663","id":"PMC_10873663","title":"Vitamin D induced up-regulation of keratinocyte growth factor (FGF-7/KGF) in MCF-7 human breast cancer cells.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10873663","citation_count":18,"is_preprint":false},{"pmid":"34671204","id":"PMC_34671204","title":"FGF7-induced E11 facilitates cell-cell communication through connexin43.","date":"2021","source":"International journal of biological 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37569486","citation_count":17,"is_preprint":false},{"pmid":"32112990","id":"PMC_32112990","title":"Hyperphosphatemia with low FGF7 and normal FGF23 and sFRP4 levels in the circulation characterizes pediatric hypophosphatasia.","date":"2020","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/32112990","citation_count":16,"is_preprint":false},{"pmid":"14527678","id":"PMC_14527678","title":"Structure-based mutational analyses in FGF7 identify new residues involved in specific interaction with FGFR2IIIb.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/14527678","citation_count":16,"is_preprint":false},{"pmid":"14981945","id":"PMC_14981945","title":"Antisense KGFR oligonucleotide inhibition of KGF-induced motility in breast cancer cells.","date":"2003","source":"Anticancer 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12203102","citation_count":16,"is_preprint":false},{"pmid":"34850536","id":"PMC_34850536","title":"FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34850536","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52335,"output_tokens":8179,"usd":0.139845},"stage2":{"model":"claude-opus-4-6","input_tokens":12139,"output_tokens":4692,"usd":0.266993},"total_usd":0.406838,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"KGF (FGF7) is a stromal cell-derived mitogen specific for epithelial cells, identified as a member of the FGF family by cDNA sequencing, with expression restricted to stromal cells of epithelial tissues.\",\n      \"method\": \"cDNA cloning, expression analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with functional characterization, foundational paper with 958 citations\",\n      \"pmids\": [\"2475908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"KGF receptor was identified as a transmembrane tyrosine kinase (FGFR2 IIIb) distinct from the basic FGF receptor, with high affinity for KGF and acidic FGF, cloned by an autocrine transformation assay in NIH/3T3 cells.\",\n      \"method\": \"Expression cDNA library cloning, receptor binding competition assay, transformation focus assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional receptor cloning with binding and signaling validation, foundational paper with 442 citations\",\n      \"pmids\": [\"1846048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"KGF receptor signaling is required for normal epidermal morphogenesis and wound reepithelialization; dominant-negative KGF receptor transgene in basal keratinocytes caused epidermal atrophy, hair follicle abnormalities, and substantially delayed wound reepithelialization with reduced keratinocyte proliferation at the wound edge.\",\n      \"method\": \"Dominant-negative transgenic mouse model, histology, proliferation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function transgenic with defined cellular phenotype, 504 citations\",\n      \"pmids\": [\"7973639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Dermatan sulfate (chondroitin sulfate B), the predominant glycosaminoglycan in skin, acts as the principal co-factor for FGF7 activity; it enables FGF7-dependent FGFR2 IIIb binding, MAPK phosphorylation, and keratinocyte proliferation, whereas heparan sulfate and chondroitin sulfate A/C do not support FGF7 activity.\",\n      \"method\": \"Cell proliferation assay (BaF/KGFR lymphoid cell line), radiolabeled FGF7 receptor binding assay, MAPK phosphorylation assay, glycosaminoglycan fractionation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal assays in a single rigorous study\",\n      \"pmids\": [\"12215437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Structure-based mutagenesis identified specific FGF7 residues (β4/β5 loop, Asp63, Leu142, Arg65) required for exclusive binding to FGFR2IIIb; mutations in these residues reduced receptor binding affinity and biological activity.\",\n      \"method\": \"Structure-based modeling, site-directed mutagenesis, receptor binding assay, biological activity assay\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with functional validation of binding specificity\",\n      \"pmids\": [\"14527678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Structural analysis reveals that FGF7 subfamily members (FGF3, FGF7, FGF10, FGF22) achieve restricted specificity for FGFR1b/FGFR2b by engaging alternatively spliced loop regions in the immunoglobulin-like domain 3 (D3) of these receptors, with weak basal receptor-binding affinity further constraining specificity.\",\n      \"method\": \"Structural analysis, comparative receptor-binding analysis\",\n      \"journal\": \"Frontiers in Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 review of structural data — strong structural basis but review article compiling existing structural evidence\",\n      \"pmids\": [\"30809251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FGF-binding protein (FGF-BP) physically interacts with FGF7, FGF10, and FGF22, and enhances the biological activity of low concentrations of these ligands; FGF-BP expression is upregulated after skin injury in keratinocytes.\",\n      \"method\": \"Co-immunoprecipitation/pulldown binding assay, in vitro activity assay, wound model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — binding demonstrated with functional enhancement, single lab study\",\n      \"pmids\": [\"15806171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KGF (FGF7) inducible expression in mouse lung activates the Akt pro-survival signaling axis in lung epithelial cells (not endothelial cells), and dominant-negative Akt blocks KGF-mediated protection from hyperoxia-induced cell death, consistent with selective KGFR expression on epithelium.\",\n      \"method\": \"Tetracycline-inducible transgenic mouse system, dominant-negative Akt mutant, in vitro and in vivo cell death assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic system with mechanistic epistasis via dominant-negative, multiple orthogonal methods\",\n      \"pmids\": [\"12732722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF signaling in thymic epithelial cells activates the p53 and NF-κB pathways and induces transcription of BMP2, BMP4, Wnt5b, and Wnt10b; canonical BMP signaling is critical for KGF-mediated TEC expansion and T-cell development.\",\n      \"method\": \"In vivo KGF administration, signaling pathway analysis, pathway inhibition experiments, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mechanistic follow-up with pathway inhibition, single lab\",\n      \"pmids\": [\"17213286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KGF/FGF7 induces lipogenesis in pulmonary epithelial H292 cells through a PI3K and JNK/SREBP-1 signaling pathway; KGF activates Akt, p70 S6K, JNK, and ERK; JNK and PI3K (but not ERK) are required for SREBP-1, FAS, and SCD-1 induction; SREBP-1 binding site in SCD-1 promoter is required for KGF effect.\",\n      \"method\": \"Pharmacological pathway inhibition (SP600125, LY294002, PD98059), luciferase promoter assays, dominant-negative and dominant-active SREBP-1 adenoviral constructs, Western blot\",\n      \"journal\": \"Journal of Lipid Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including promoter mutagenesis and dominant constructs in a single study\",\n      \"pmids\": [\"16162944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KGF promotes ductal cell proliferation through the MEK-ERK1/2 pathway and ductal cell differentiation (PDX1, Glut2 expression) through a PI3K/AKT-dependent mechanism in pancreatic duct cells, contributing to beta-cell neogenesis.\",\n      \"method\": \"BrdU incorporation assay, pharmacological MEK inhibition (in vitro and in vivo), morpholino antisense against MEK1, PI3K inhibition, immunolocalization\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic epistasis with defined cellular readouts, in vitro and in vivo\",\n      \"pmids\": [\"19266047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF-induced retention of alveolar type II cell phenotype (preventing transdifferentiation to type I-like cells) is mediated specifically by JNK activation and downstream c-Jun phosphorylation; inhibition of JNK (but not ERK1/2 or p38) abrogates this effect, and overexpression of JNKK2 promotes AT2 phenotype markers.\",\n      \"method\": \"Primary rat AEC culture, selective MAPK inhibitors, JNKK2 overexpression, immunoblot, monoclonal antibody phenotyping\",\n      \"journal\": \"American Journal of Respiratory Cell and Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic epistasis with clean phenotypic readout\",\n      \"pmids\": [\"17872496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KGF protects airway epithelial cells against H2O2-induced permeability increase and disruption of F-actin cytoskeleton via a PKC-dependent mechanism; calphostin C (PKC inhibitor) abolishes both the KGF-mediated decrease in basal albumin flux and protection against H2O2.\",\n      \"method\": \"Transwell permeability assay, pharmacological PKC inhibition, F-actin immunostaining\",\n      \"journal\": \"American Journal of Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with defined functional readout and cytoskeletal mechanism\",\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 (blocked by aphidicolin and butylphenyl dGTP but not dideoxythymidine triphosphate, ruling out polymerase-β).\",\n      \"method\": \"Alkaline unwinding DNA damage assay, selective DNA polymerase inhibitors\",\n      \"journal\": \"American Journal of Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with multiple inhibitors defining the DNA repair mechanism\",\n      \"pmids\": [\"9227520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"KGF upregulates active Na+ transport across alveolar epithelial cell monolayers by increasing Na+/K+-ATPase α1 subunit mRNA and protein (α1 and β1 subunit protein), without increasing rENaC subunit mRNAs (which actually decrease), suggesting Na pump upregulation as the primary mechanism.\",\n      \"method\": \"Short-circuit current measurement, quantitative mRNA assay, Western blot\",\n      \"journal\": \"American Journal of Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss/gain-of-function with defined molecular and functional readouts\",\n      \"pmids\": [\"9458813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KGF promotes limbal epithelial outgrowth by inducing ΔNp63α expression through the p38 MAPK pathway; inhibition of p38 blocks KGF-induced ΔNp63α upregulation, and knockdown of ΔNp63α significantly reduces KGF-induced outgrowth.\",\n      \"method\": \"Ex vivo limbal explant culture, kinase inhibitor studies, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic epistasis with defined downstream transcription factor\",\n      \"pmids\": [\"19920075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KGF suppresses α2β1 integrin expression and function in prostatic epithelial transient amplifying population (TAP) cells, inducing differentiation (PAP, CK18, androgen receptor expression) via p38-MAPK; p38 inhibitor (SB202190) blocks KGF-induced differentiation.\",\n      \"method\": \"Primary human prostate epithelial culture, flow cytometry, immunofluorescence, pharmacological p38 inhibition, FGFR2 expression analysis by FACS\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with defined differentiation phenotype in primary human cells\",\n      \"pmids\": [\"16554439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGF7/KGF induces autophagy in human keratinocytes via a PI3K-AKT-MTOR-independent pathway, stimulating autophagosome formation; upon prolonged stimulus, FGF7 also accelerates autophagosome turnover. Autophagy is required for FGF7-mediated early differentiation (KRT1/K1 upregulation), as shown by 3-MA, BECN1, and ATG5 depletion.\",\n      \"method\": \"Quantitative fluorescence assays of autophagy, selective autophagy inhibitors (3-MA, bafilomycin A1), siRNA knockdown of BECN1 and ATG5, Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic knockdown and pharmacological inhibition with functional readout\",\n      \"pmids\": [\"24577098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGF7 localizes to inhibitory postsynaptic sites in hippocampal neurons and functions as a presynaptic organizer for inhibitory (but not excitatory) synapse differentiation; its selective inhibitory synaptic targeting requires the motor protein KIF5 and the adaptor protein gephyrin for microtubule transport, with FGF7 co-transported with gephyrin as shown by time-lapse imaging.\",\n      \"method\": \"Time-lapse live imaging, co-localization assays, dominant-negative motor protein experiments, immunofluorescence, siRNA knockdown\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live imaging of transport, motor protein epistasis, established synaptic function with specific molecular machinery\",\n      \"pmids\": [\"25431136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Increased KGF expression induces fibroblast activation through a double paracrine loop: KGF stimulates keratinocytes to produce and secrete oncostatin M (OSM), which then activates fibroblasts (collagen I-α1 upregulation, increased migration) via OSM-regulated STAT3 phosphorylation and urokinase plasminogen activator expression.\",\n      \"method\": \"Co-culture systems, ELISA, Western blot (STAT3 phosphorylation), siRNA knockdown, migration assays\",\n      \"journal\": \"Journal of Investigative Dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — paracrine loop mechanistically dissected with molecular readouts, single lab\",\n      \"pmids\": [\"23096718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KGF-1 promotes wound contraction via a double-paracrine mechanism: KGF-1 stimulates keratinocytes to secrete TGF-β1, which then activates fibroblasts to contract collagen lattices; TGF-β1 neutralizing antibody attenuates KGF-1-induced fibroblast contraction, and this involves the TGF-β1/Smad2/3 pathway with α-SMA and collagen I upregulation.\",\n      \"method\": \"Keratinocyte-fibroblast co-culture, fibroblast-populated collagen lattice (FPCL) contraction assay, ELISA (TGF-β1), Western blot (p-Smad2/3, α-SMA, Col-I), TGF-β1 neutralizing antibody, diabetic rat wound model\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, neutralizing antibody epistasis, in vitro and in vivo validation\",\n      \"pmids\": [\"30894415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF-induced motility of breast cancer cells requires Grb2 (an adaptor protein) and ERK1/2 activation downstream of the KGF receptor tyrosine kinase; Grb2 knockdown and ERK1/2 inhibition (PD98059) suppress KGF-induced motility, whereas Akt inhibition (wortmannin) does not.\",\n      \"method\": \"Antisense/siRNA knockdown of Grb2, pharmacological ERK and Akt inhibition, wounding motility assay, cDNA microarray\",\n      \"journal\": \"Clinical & Experimental Metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown plus pharmacological epistasis with defined functional readout\",\n      \"pmids\": [\"15672868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-1α produced by prostatic epithelial cells acts as a paracrine inducer of FGF7 expression in prostatic stromal cells; blocking with anti-IL-1α antibodies or IL-1Ra abrogates the epithelial conditioned medium-induced FGF7 upregulation in stroma, establishing a double paracrine loop.\",\n      \"method\": \"Conditioned medium experiments, neutralizing antibody blocking, ELISA, immunohistochemistry\",\n      \"journal\": \"American Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — neutralizing antibody epistasis with molecular readout identifying the upstream inducer of FGF7\",\n      \"pmids\": [\"10880394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"KGF can replace testosterone as a paracrine mediator of ductal branching morphogenesis in rat ventral prostate; KGF is expressed in prostatic mesenchyme and its receptor exclusively in epithelium; neutralization of endogenous KGF with anti-KGF antibody or soluble KGFR inhibits androgen-stimulated growth and reduces ductal end buds.\",\n      \"method\": \"RT-PCR expression analysis, in situ hybridization, organ culture with neutralizing antibody and soluble receptor peptide, DNA content assay\",\n      \"journal\": \"International Journal of Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor localization plus loss-of-function with neutralizing antibody and soluble receptor, defined morphological readout\",\n      \"pmids\": [\"8946242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GLP-1 receptor signaling promotes intestinal mucosal growth through FGF7; exendin-4 increases Fgf7 expression, and intestinal growth response to exendin-4 is absent in Fgf7-/- mice, placing FGF7 downstream of GLP-1R in intestinal mucosal expansion.\",\n      \"method\": \"Glp1r-/- and Fgf7-/- mouse genetic epistasis, exendin-4 treatment, gene expression analysis, intestinal morphometry\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with two knockout models and defined pathway position\",\n      \"pmids\": [\"25738454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF7/FGFR2 signaling promotes invasion and migration of gastric cancer cells through upregulation of THBS1 (thrombospondin-1) via the PI3K/Akt/mTOR pathway; FGFR2 or THBS1 knockdown suppresses FGF7-induced invasion/migration.\",\n      \"method\": \"siRNA knockdown of FGFR2 and THBS1, invasion/migration assays, PI3K/Akt/mTOR pathway inhibitor studies, Western blot\",\n      \"journal\": \"International Journal of Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with pharmacological epistasis and defined invasion readout\",\n      \"pmids\": [\"28339036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FGF7 promotes osteocyte cell processes by inducing β-catenin cytoplasmic accumulation and nuclear translocation, which increases connexin43 (Cx43) expression and gap junction formation between osteocytes.\",\n      \"method\": \"Western blot, immunofluorescence (β-catenin nuclear translocation), gap junction/cell process assays in MLO-Y4 cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established with β-catenin localization and Cx43 functional readout, single lab\",\n      \"pmids\": [\"30287900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF7 promotes osteoblast dendrite elongation and gap junctional intercellular communication (GJIC) by inducing E11 expression; E11 directly interacts with connexin43 (Cx43) in primary osteoblasts; MAPK and PI3K-AKT pathways are involved.\",\n      \"method\": \"Western blot, immunofluorescence, co-immunoprecipitation (E11-Cx43 interaction), GJIC functional assay, pathway inhibition\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP for E11-Cx43 interaction plus pathway inhibition and functional GJIC readout\",\n      \"pmids\": [\"34671204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fibro-adipogenic progenitors (FAPs) signal to muscle satellite cells (MuSCs) via FGF7-FGFR2; exogenous FGF7 promotes MuSC proliferation and muscle regeneration, and FGFR2 knockdown abolishes FGF7-induced proliferation.\",\n      \"method\": \"Single-cell RNA sequencing, CellChat ligand-receptor analysis, EdU proliferation assay, FGFR2 siRNA knockdown, cardiotoxin injury and d-galactose aging models in vivo\",\n      \"journal\": \"Journal of Cachexia, Sarcopenia and Muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq cell communication validated by receptor knockdown and in vivo functional assays\",\n      \"pmids\": [\"38751367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX9, induced by WNT3A-TCF7 signaling, transcriptionally upregulates both FGF7 and FGFR2 in cholangiocarcinoma; FGF7 is secreted and activates FGFR2 in an autocrine pathway, promoting CCA proliferation and pemigatinib resistance; neutralizing FGF7 or inhibiting HIF-1α reverses FGF7-mediated EMT.\",\n      \"method\": \"mRNA sequencing, in vitro/in vivo validation, WNT3A stimulation assays, FGF7 neutralizing antibody, HIF-1α pathway inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway from Wnt to FGF7 autocrine loop with neutralizing antibody functional validation\",\n      \"pmids\": [\"35428876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF7-FGFR2 autocrine signaling in fusion-gene-positive (PAX3-FOXO1) rhabdomyosarcoma sustains MAPK activity and promotes cell viability and chemoresistance; genetic silencing of FGFR2 or FGF7 decreases cell viability, and pharmacological FGFR inhibition reduces tumor growth in vivo.\",\n      \"method\": \"siRNA knockdown of FGFR2 and FGF7, MAPK activity assay, FGFR inhibitor (NVP-BGJ398), xenograft tumor model\",\n      \"journal\": \"Molecular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis with in vitro and in vivo functional readouts\",\n      \"pmids\": [\"34850536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAF-derived FGF7 inhibits ubiquitination and degradation of HIF-1α via FGFR2 interaction in ovarian cancer cells, activating HIF-1α-dependent EMT; neutralizing antibodies against FGF7 substantially reduce tumor growth in vivo.\",\n      \"method\": \"Single-cell transcriptomic analysis, in vitro FGFR2 binding assays, HIF-1α ubiquitination assay, neutralizing antibody treatment, xenograft model\",\n      \"journal\": \"Journal of Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (FGF7/FGFR2/HIF-1α/EMT) supported by multiple in vitro methods and in vivo antibody validation\",\n      \"pmids\": [\"38491511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The KGF/FGF7 promoter is androgen-regulated; transient transfection in LNCaP cells with the synthetic androgen R1881 upregulated KGF promoter activity 6–11-fold, with androgen-responsive elements mapping to the region -900 to -1200.\",\n      \"method\": \"Promoter-reporter transfection assay, androgen stimulation\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter-reporter functional assay with defined responsive region, single lab\",\n      \"pmids\": [\"8607856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KGF promotes integrin α5 expression in keratinocytes by inducing sustained ERK1/2-dependent phosphorylation of C/EBP-β transcription factor; dominant-negative C/EBP-β inhibits α5 promoter activity and C/EBP-β siRNA reduces integrin α5 expression.\",\n      \"method\": \"Promoter-reporter assay, dominant-negative C/EBP-β, siRNA knockdown, Western blot (ERK1/2, C/EBP-β phosphorylation), 3D epidermal tissue analogues\",\n      \"journal\": \"American Journal of Physiology - Cell Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter-reporter with genetic epistasis (DN construct and siRNA), multiple orthogonal approaches\",\n      \"pmids\": [\"17596295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In salivary gland branching morphogenesis, FGF7 and EGF produce distinct morphological outcomes: EGF induces lobule formation and cleft formation, while FGF7 promotes stalk elongation associated with differential cell proliferation (higher in distal regions); these effects correlate with spatially distinct patterns of FGFR expression.\",\n      \"method\": \"Mesenchyme-free salivary epithelial explant culture, BrdU labeling, whole-mount analysis\",\n      \"journal\": \"Developmental Dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined morphological phenotypes with BrdU proliferation mapping in functional organ culture\",\n      \"pmids\": [\"10373019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"AS101-induced hair growth is mediated by KGF; anti-KGF neutralizing antibodies and dominant-negative KGF receptor transgene abolish the AS101-induced anagen; AS101 upregulates KGF expression in fibroblasts via the Ras signaling pathway.\",\n      \"method\": \"Neutralizing antibody, dominant-negative transgenic mouse, fibroblast culture with Ras pathway analysis\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody and genetic epistasis placing KGF downstream of Ras in hair growth induction\",\n      \"pmids\": [\"14656992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGF7 (KGF) is a mesenchyme-derived, heparin-binding growth factor that acts exclusively through FGFR2 IIIb (the KGF receptor) on epithelial cells, using dermatan sulfate as its principal co-receptor in skin; its β4/β5 loop and specific residues (Asp63, Leu142, Arg65) confer exclusive FGFR2IIIb binding specificity; downstream signaling activates PI3K/Akt, ERK1/2, JNK, and p38 MAPK in a context-dependent manner to drive epithelial proliferation, differentiation, survival, autophagy, and cytoskeletal reorganization; in the nervous system FGF7 localizes to inhibitory postsynaptic sites via KIF5/gephyrin-mediated transport to organize inhibitory presynaptic differentiation; and in various tissues it operates through double paracrine loops (e.g., with TGF-β1 and IL-1α) and autocrine FGFR2 signaling to regulate organ morphogenesis, wound healing, thymic regeneration, and tumor progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FGF7 (also known as KGF) is a mesenchyme-derived paracrine growth factor that signals exclusively through the epithelial-specific receptor FGFR2 IIIb to drive epithelial proliferation, differentiation, survival, and morphogenesis across diverse tissues including skin, lung, prostate, intestine, and thymus [PMID:2475908, PMID:1846048, PMID:7973639]. Receptor specificity is conferred by FGF7's β4/β5 loop and residues Asp63, Leu142, and Arg65 engaging the alternatively spliced D3 domain of FGFR2b, with dermatan sulfate serving as the principal glycosaminoglycan co-receptor in skin [PMID:14527678, PMID:12215437]. Downstream, FGF7 activates PI3K/Akt, ERK1/2, JNK, and p38 MAPK in a context-dependent manner — ERK drives proliferation and motility, PI3K/Akt mediates survival and differentiation, JNK controls epithelial phenotype maintenance and lipogenesis, and p38 governs progenitor cell differentiation — while also inducing autophagy-dependent keratinocyte differentiation and double paracrine loops (via TGF-β1, OSM, or IL-1α) that coordinate epithelial–mesenchymal crosstalk in wound healing and tissue remodeling [PMID:12732722, PMID:16162944, PMID:17872496, PMID:16554439, PMID:24577098, PMID:30894415, PMID:23096718]. Beyond epithelial tissues, FGF7 functions in hippocampal neurons where it is transported to inhibitory postsynaptic sites via KIF5/gephyrin-mediated microtubule transport to organize inhibitory presynaptic differentiation [PMID:25431136].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"The identity of a stromal-derived epithelial mitogen was unknown; cloning FGF7/KGF from fibroblast-conditioned medium established it as a novel FGF family member with expression restricted to stromal cells of epithelial tissues, defining the mesenchymal-to-epithelial paracrine paradigm.\",\n      \"evidence\": \"cDNA cloning and expression analysis from human fibroblast-conditioned medium\",\n      \"pmids\": [\"2475908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No receptor identified\", \"Downstream signaling unknown\", \"In vivo function not established\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"The receptor mediating KGF's epithelial specificity was unknown; identification of FGFR2 IIIb as the KGF receptor explained why KGF acts exclusively on epithelial cells that express this splice variant.\",\n      \"evidence\": \"Expression cDNA library screen with autocrine transformation assay in NIH/3T3 cells, receptor binding competition\",\n      \"pmids\": [\"1846048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for receptor selectivity unknown\", \"Co-receptor requirements not defined\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Whether KGF receptor signaling was required for epithelial homeostasis in vivo was untested; dominant-negative KGFR in transgenic mice demonstrated that this pathway is essential for normal epidermal morphogenesis, hair follicle development, and wound reepithelialization.\",\n      \"evidence\": \"Dominant-negative KGFR transgenic mouse, histology and proliferation assays at wound edges\",\n      \"pmids\": [\"7973639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathways not dissected\", \"Relative contribution of FGF7 versus other FGFR2b ligands (FGF10, FGF22) not resolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The role of FGF7 in organ morphogenesis beyond skin was unclear; work in prostate organ culture showed FGF7 mediates androgen-driven ductal branching morphogenesis via mesenchyme-epithelium paracrine signaling, and its promoter contains androgen-responsive elements.\",\n      \"evidence\": \"Prostate organ culture with anti-KGF neutralizing antibody and soluble KGFR; promoter-reporter assays with androgen stimulation in LNCaP cells\",\n      \"pmids\": [\"8946242\", \"8607856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Androgen-responsive element identity not fully mapped\", \"Whether other FGFs compensate in vivo unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The cytoprotective mechanisms downstream of KGF were undefined; studies in airway epithelial cells revealed PKC-dependent barrier protection and F-actin stabilization, and enhanced DNA repair capacity through replicative DNA polymerases α, δ, and ε.\",\n      \"evidence\": \"Transwell permeability with PKC inhibitors; alkaline unwinding DNA damage assay with selective polymerase inhibitors in pulmonary epithelial cells\",\n      \"pmids\": [\"9142942\", \"9227520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PKC isoform not identified\", \"Connection between DNA repair induction and receptor signaling cascades not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The glycosaminoglycan co-receptor for FGF7 was assumed to be heparan sulfate by analogy with other FGFs; dermatan sulfate was identified as the principal co-receptor in skin, uniquely enabling FGFR2 IIIb binding, MAPK activation, and keratinocyte proliferation.\",\n      \"evidence\": \"Reconstituted receptor binding, MAPK phosphorylation, and proliferation assays with fractionated GAGs in BaF/KGFR cells\",\n      \"pmids\": [\"12215437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dermatan sulfate–FGF7 interaction not resolved\", \"Whether other tissues use different co-receptor GAGs unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The structural determinants of FGF7's exclusive FGFR2b specificity were unknown; structure-based mutagenesis identified the β4/β5 loop and residues Asp63, Leu142, and Arg65 as critical for receptor binding and biological activity.\",\n      \"evidence\": \"Site-directed mutagenesis guided by structural modeling, receptor binding and activity assays\",\n      \"pmids\": [\"14527678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of FGF7–FGFR2b complex at that time\", \"Contribution of each residue to affinity versus specificity not fully deconvolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"How KGF protects epithelial cells from oxidative death was mechanistically undefined; inducible KGF expression in mouse lung demonstrated PI3K/Akt activation selectively in epithelial cells, and dominant-negative Akt blocked KGF-mediated protection from hyperoxia.\",\n      \"evidence\": \"Tetracycline-inducible KGF transgenic mice, dominant-negative Akt, in vivo and in vitro cell death assays\",\n      \"pmids\": [\"12732722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream Akt substrates mediating survival not identified\", \"Whether Akt is required for all KGF cytoprotective effects unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Context-dependent divergence of MAPK branches downstream of KGF was unresolved; JNK and PI3K (but not ERK) were shown to drive KGF-induced lipogenesis via SREBP-1 in pulmonary epithelial cells, while ERK drove proliferation and motility in other contexts.\",\n      \"evidence\": \"Pharmacological inhibitors, dominant-negative/active SREBP-1 constructs, promoter mutagenesis in H292 cells; Grb2 knockdown and ERK inhibition in breast cancer motility assays\",\n      \"pmids\": [\"16162944\", \"15672868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the same receptor activates different MAPK branches in different cell types not explained\", \"In vivo relevance of KGF-driven lipogenesis not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"How KGF maintains epithelial cell identity versus driving differentiation through specific MAPK branches was unclear; JNK/c-Jun was shown to maintain alveolar type II cell phenotype, p38 was shown to drive prostatic and limbal epithelial differentiation, and ERK-C/EBPβ controlled integrin α5 expression in keratinocytes.\",\n      \"evidence\": \"Selective MAPK inhibitors with JNKK2 overexpression in primary rat AECs; p38 inhibitor and siRNA in prostate TAP cells and limbal explants; DN-C/EBPβ and siRNA in keratinocytes\",\n      \"pmids\": [\"17872496\", \"16554439\", \"19920075\", \"17596295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How pathway selection is determined at the receptor level unknown\", \"Cross-talk between JNK, p38, and ERK branches not dissected\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Upstream regulators and paracrine feedback circuits controlling FGF7 expression were incompletely defined; IL-1α from prostatic epithelial cells was identified as the paracrine inducer of FGF7 in stromal cells, establishing a double paracrine loop.\",\n      \"evidence\": \"Conditioned medium with anti-IL-1α neutralizing antibodies and IL-1Ra in prostatic cell co-cultures\",\n      \"pmids\": [\"10880394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-1α–FGF7 loop operates in non-prostatic tissues not tested\", \"Transcription factors mediating IL-1α induction of FGF7 not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The mechanism by which KGF coordinates epithelial-mesenchymal crosstalk beyond direct epithelial stimulation was unclear; KGF was shown to induce keratinocyte secretion of oncostatin M, which activates fibroblasts via STAT3 to promote collagen and migration — a double paracrine wound-healing circuit.\",\n      \"evidence\": \"Keratinocyte-fibroblast co-culture, STAT3 phosphorylation, siRNA knockdown, migration assays\",\n      \"pmids\": [\"23096718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OSM loop operates in vivo during wound healing not confirmed\", \"Other keratinocyte-derived mediators in this circuit not explored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether FGF7 induces autophagy and how autophagy relates to keratinocyte differentiation was unknown; FGF7 was shown to stimulate mTOR-independent autophagy in keratinocytes, and BECN1/ATG5-dependent autophagy was required for FGF7-induced early differentiation (K1 expression).\",\n      \"evidence\": \"Autophagy flux assays, 3-MA and bafilomycin A1 treatment, BECN1 and ATG5 siRNA in human keratinocytes\",\n      \"pmids\": [\"24577098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal connecting FGFR2b to autophagy initiation not identified\", \"In vivo relevance of autophagy for FGF7-driven differentiation untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How FGF7 functions outside epithelial tissues was largely unknown; in hippocampal neurons, FGF7 was found to localize selectively to inhibitory postsynaptic sites via KIF5/gephyrin-mediated microtubule transport and to organize inhibitory (not excitatory) presynaptic differentiation.\",\n      \"evidence\": \"Time-lapse live imaging of FGF7-gephyrin co-transport, dominant-negative motor protein experiments, co-localization, siRNA in hippocampal neurons\",\n      \"pmids\": [\"25431136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FGF7 acts through FGFR2b or another receptor at synapses not determined\", \"Mechanism by which FGF7 organizes presynaptic vesicle clustering not elucidated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The upstream signals inducing FGF7 in the intestinal niche were unknown; GLP-1 receptor signaling was shown to require FGF7 for intestinal mucosal growth, as Fgf7-/- mice failed to respond to exendin-4.\",\n      \"evidence\": \"Genetic epistasis with Fgf7-/- and Glp1r-/- mice, exendin-4 treatment, intestinal morphometry\",\n      \"pmids\": [\"25738454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type producing FGF7 downstream of GLP-1R not definitively identified\", \"Whether this pathway operates in human intestine not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The mechanism by which KGF drives wound contraction was unclear; KGF was shown to stimulate keratinocyte TGF-β1 secretion, which activates fibroblast contraction via Smad2/3-dependent α-SMA and collagen I upregulation, validated by TGF-β1 neutralizing antibody in vitro and in a diabetic rat wound model.\",\n      \"evidence\": \"Keratinocyte-fibroblast co-culture, FPCL contraction, TGF-β1 ELISA, neutralizing antibody, diabetic rat wound model\",\n      \"pmids\": [\"30894415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this loop is the dominant wound contraction mechanism versus other pathways not established\", \"Diabetic-specific versus general wound context not fully dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether FGF7-FGFR2 autocrine signaling operates in cancer cells (beyond paracrine) and contributes to therapy resistance was unclear; autocrine FGF7-FGFR2 loops were demonstrated in PAX3-FOXO1 rhabdomyosarcoma sustaining MAPK and viability, and in cholangiocarcinoma where SOX9 transcriptionally drives both FGF7 and FGFR2, promoting pemigatinib resistance.\",\n      \"evidence\": \"siRNA knockdown of FGF7 and FGFR2, FGFR inhibitors, xenograft models; WNT3A-SOX9 axis mapping and FGF7 neutralizing antibody in CCA\",\n      \"pmids\": [\"34850536\", \"35428876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autocrine FGF7 loops are general features of FGFR2-amplified cancers not determined\", \"Patient-derived validation limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether FGF7 plays a paracrine role in muscle regeneration was untested; fibro-adipogenic progenitor-derived FGF7 was shown to promote muscle satellite cell proliferation via FGFR2, with FGFR2 knockdown abolishing the proliferative response.\",\n      \"evidence\": \"scRNA-seq with CellChat, EdU proliferation, FGFR2 siRNA, cardiotoxin injury and aging models in vivo\",\n      \"pmids\": [\"38751367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FGF7 or FGF10 is the dominant FGFR2b ligand in muscle regeneration not resolved\", \"Downstream signaling in satellite cells not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how the same FGFR2b receptor selectively activates different MAPK branches in different cell types; the structural basis of dermatan sulfate co-receptor function; whether FGF7's neuronal synapse-organizing function acts through FGFR2b; and the full scope of autocrine FGF7-FGFR2 signaling in therapy-resistant cancers.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure of FGF7–dermatan sulfate–FGFR2b ternary complex\", \"Mechanism of context-dependent MAPK branch selection downstream of FGFR2b not resolved\", \"Receptor identity for neuronal FGF7 synapse function not confirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 20, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 19, 20, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 9, 10, 11, 15, 16, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 23, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [25, 29, 30, 31]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FGFR2\",\n      \"KIF5\",\n      \"GPHN\",\n      \"GRB2\",\n      \"FGFBP1\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}