{"gene":"FGFR2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"ESRP1 and ESRP2 are epithelial cell-type-specific RNA-binding proteins that regulate mutually exclusive alternative splicing of FGFR2 exons IIIb (epithelial) and IIIc (mesenchymal). Ectopic expression of either ESRP in IIIc-expressing cells switches endogenous FGFR2 splicing to the IIIb isoform; knockdown of both ESRPs in IIIb-expressing cells switches splicing to IIIc.","method":"cDNA expression screening, ectopic overexpression, RNAi knockdown in cell lines","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional gain- and loss-of-function experiments, replicated across multiple cell lines","pmids":["19285943"],"is_preprint":false},{"year":2008,"finding":"Somatic FGFR2 mutations found in endometrial carcinoma are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells; inhibition of FGFR2 kinase activity in endometrial cancer cell lines bearing these mutations inhibits transformation and survival.","method":"NIH 3T3 transformation assay, small-molecule kinase inhibition in mutant cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional transformation assay plus selective pharmacological inhibition with defined cellular phenotype","pmids":["18552176"],"is_preprint":false},{"year":2008,"finding":"In FGFR2-amplified gastric cancer cell lines, FGFR2 is constitutively tyrosine-phosphorylated and drives phosphorylation of EGFR family members (EGFR, HER2, ErbB3). FGFR2 kinase inhibition abolishes EGFR/HER2/ErbB3 phosphorylation, placing FGFR2 upstream of the EGFR pathway. shRNA to ErbB3 confirms a functional role for this downstream activation in proliferation.","method":"FGFR2-selective small-molecule inhibitor, shRNA knockdown, phosphotyrosine immunoblotting in amplified cell lines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic (shRNA) approaches, reciprocal phospho-immunoblotting establishing upstream-downstream order","pmids":["18381441"],"is_preprint":false},{"year":2005,"finding":"Activating FGFR2 mutations (C342Y or S252W) and exogenous FGF in osteoblasts induce Sox2 expression, which associates with β-catenin and inhibits Wnt-responsive transcription through its C-terminal domain, thereby suppressing Wnt target gene expression and osteoblast differentiation.","method":"Gene expression profiling, constitutive Sox2 expression, reporter assay, co-immunoprecipitation of Sox2–β-catenin","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (expression profiling, reporter assay, Co-IP, in vivo expression), single lab but rigorous","pmids":["15781477"],"is_preprint":false},{"year":2013,"finding":"The adaptor protein Grb2 controls FGFR2 phosphorylation homeostasis by simultaneously inhibiting FGFR2 kinase activity and Shp2 phosphatase activity through direct receptor binding. FGFR2 phosphorylates Grb2, releasing it from the receptor and allowing both FGFR2 kinase and Shp2 phosphatase activity to increase; Shp2 dephosphorylates Grb2 to restore the inhibitory complex.","method":"In vitro kinase/phosphatase assays, FLIM-FRET, Co-IP, mutagenesis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assays combined with FRET-based live-cell measurements and mutagenesis, single lab but multiple orthogonal methods","pmids":["23420874"],"is_preprint":false},{"year":2014,"finding":"In non-stimulated FGFR2-expressing cancer cells, the SH3 domain of PLCγ1 directly competes with the C-terminal SH3 domain of Grb2 for a phosphorylation-independent binding site at the very C-terminus of FGFR2. Reduced Grb2 concentration permits PLCγ1 recruitment, upregulating basal phospholipase C activity, PIP2 turnover, intracellular calcium, cell motility, and invasion.","method":"In vitro binding competition assay, NMR/biochemical mapping of binding site, phospholipase activity assay, calcium imaging, invasion assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of competition, structural mapping, and functional cellular readouts in a single study","pmids":["24440983"],"is_preprint":false},{"year":2006,"finding":"The craniosynostosis mutation FGFR2-C278F results in diminished N-linked glycosylation, increased proteasomal/lysosomal degradation, and restricted subcellular localization (ER retention). Both the C278F mutant and unglycosylated wild-type FGFR2 activate PLCγ and show increased binding to Frs2 in a ligand-independent manner from intracellular compartments, demonstrating that autoactive FGFR2 can signal from the ER.","method":"Glycosylation inhibition, subcellular fractionation, ubiquitination assay, PLCγ phosphorylation assay, Frs2 co-immunoprecipitation in osteoblastic cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (glycosylation, fractionation, Co-IP, signaling assays) in a single lab","pmids":["16844695"],"is_preprint":false},{"year":1992,"finding":"The K-sam (FGFR2) gene expresses at least four classes of mRNA encoding: (1) a full-length transmembrane receptor tyrosine kinase, (2) a secreted receptor retaining the tyrosine kinase domain, and (3) a secreted receptor lacking the tyrosine kinase domain, demonstrating that FGFR2 produces both membrane-bound and secreted receptor forms.","method":"RNA blot analysis with multiple probes, cDNA isolation and sequencing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA cloning and sequencing with Northern blot validation, single lab","pmids":["1313574"],"is_preprint":false},{"year":2008,"finding":"FGF10 induces migration and invasion of pancreatic cancer cells specifically through interaction with the FGFR2-IIIb isoform, and concurrently induces expression of MT1-MMP mRNA and TGF-β1 mRNA and increased TGF-β1 secretion.","method":"Migration/invasion assays with recombinant FGF10, isoform-specific receptor identification, RT-PCR for MT1-MMP and TGF-β1, ELISA for TGF-β1 protein","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with ligand stimulation plus downstream gene expression, isoform specificity established, single lab","pmids":["18594526"],"is_preprint":false},{"year":2018,"finding":"NEGR1 physically interacts with FGFR2, decreases FGFR2 degradation from the plasma membrane, and modulates FGFR2-dependent ERK and AKT signaling. NEGR1 knockdown reduces spine density and neuronal migration similarly to FGFR2 knockdown; FGFR2 overexpression rescues all defects caused by NEGR1 knockdown in vivo, placing NEGR1 upstream of FGFR2.","method":"Co-immunoprecipitation, in vivo cortical electroporation knockdown/rescue, Western blotting for p-ERK and p-AKT, FGFR2 surface degradation assay","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus in vivo epistasis rescue experiment with multiple signaling readouts","pmids":["30059965"],"is_preprint":false},{"year":2022,"finding":"Truncation of FGFR2 exon 18 (FGFR2ΔE18), generated by diverse structural alterations (rearrangements, partial amplifications, nonsense/frameshift mutations), is a potent single-driver oncogenic mutation; full-length FGFR2 amplification requires cooperating driver genes for oncogenic competence. FGFR2ΔE18 variants are sensitive to FGFR-targeted therapy in mouse and human tumor models.","method":"Transposon-based in vivo screen, tumor modelling in mice, in vitro functional compendium of FGFR2 variants, preclinical xenograft models, clinical trial correlation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic screen plus multi-model functional validation and clinical correlation","pmids":["35948633"],"is_preprint":false},{"year":2019,"finding":"Tumor-associated fibroblasts produce FGF5, which activates FGFR2 in breast cancer cells; FGFR2 then transactivates HER2 via c-Src, causing resistance to HER2-targeted therapies. FGFR2 inhibition abrogates this pathway and re-sensitizes resistant cells to HER2 therapy in vitro and in vivo.","method":"Co-culture of TAFs and cancer cells, FGFR2 inhibitor treatment, shRNA knockdown, phospho-immunoblotting for c-Src and HER2, mouse xenograft co-injection","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with in vitro and in vivo confirmation, single lab","pmids":["31699826"],"is_preprint":false},{"year":2021,"finding":"FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids toward cholangiocarcinoma on a Tp53-/- background via Ras-Erk signaling. Dual FGFR2 inhibition + MEK1/2 inhibition is more effective than single-agent FGFR inhibition in vitro and in vivo, demonstrating epistatic dependence of FGFR2 fusions on Ras-ERK signaling.","method":"Liver organoid transduction, mouse transplantation, MEK inhibitor combination experiments, in vitro and in vivo pharmacology","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (organoid/transplant model) plus pharmacological epistasis, in vitro and in vivo, multiple fusion variants tested","pmids":["33741397"],"is_preprint":false},{"year":2017,"finding":"FGFR2c isoform (not FGFR2b) is specifically required for male sex determination in mice. XY Fgfr2c-/- gonads show complete male-to-female sex reversal with ectopic FOXL2 expression; ablation of Foxl2 partially rescues sex reversal, placing FGFR2c upstream of FOXL2 repression in testis determination.","method":"Conditional Fgfr2c knockout mice, genetic epistasis with Foxl2 knockout, immunofluorescence for SOX9/FOXL2 markers","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific conditional knockout plus Foxl2 epistasis rescue experiment with clear molecular readouts","pmids":["28938467"],"is_preprint":false},{"year":2017,"finding":"DeltaNp63 directly regulates FGFR2-IIIb expression in thymic epithelial cells via interaction with APOBEC1-binding protein 1; FGFR2-IIIb knockout mice show thymic defects similar to p63-/- mice, placing FGFR2-IIIb as a downstream effector of DeltaNp63 in thymic development.","method":"p63-/- mouse genetic complementation with TAp63 or DeltaNp63 transgenes, Fgfr2-IIIb knockout mice, chromatin interaction analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation epistasis plus knockout phenotype comparison, single lab","pmids":["17626181"],"is_preprint":false},{"year":2023,"finding":"PTPN9 directly dephosphorylates FGFR2 at pY656/657. PTPN9 interacts with FGFR2 via ACAP1 mediation; the sec14p domain of PTPN9 binds FGFR2 through ACAP1's PH and Arf-GAP domains. Key amino acids (YRETRRKE motif, Y471 of PTPN9) are required for the interaction. PTPN9 overexpression synergistically enhances pemigatinib effectiveness in CCA models including PDX.","method":"Phosphatase activity assay, FGFR2-PTPN9 structural modeling, Co-IP, mutagenesis of interaction sites, in vitro and PDX pharmacology","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — phosphatase substrate assay, structural modeling, mutagenesis, and in vivo PDX, single lab","pmids":["37505213"],"is_preprint":false},{"year":2011,"finding":"Conditional deletion of Fgfr2 in the ureteric bud causes severe ureteric branching defects. Combining Fgfr2 deletion with Frs2α deletion produces more severe defects than either single knockout at later stages, but is equivalent to Fgfr2 deletion alone at E13.5. Point mutations in the Frs2α binding site of Fgfr2 do not phenocopy Fgfr2 deletion, indicating that Fgfr2 acts via Frs2α-independent pathways in the ureteric epithelium.","method":"Conditional knockout mice (Hoxb7-Cre), compound Fgfr2/Frs2α knockout, point mutation knock-in (Fgfr2LR/LR), 3D ureteric reconstruction","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic models with clear morphological phenotype comparison, single lab","pmids":["21350013"],"is_preprint":false},{"year":2020,"finding":"Inducible inactivation of Fgfr2 (but not Fgfr3) specifically in SPC+ type II alveolar epithelial cells causes increased mortality and lung injury after bleomycin administration and loss of AEC2s, demonstrating that AEC2-specific FGFR2 signaling is required for AEC2 survival and homeostasis after lung injury.","method":"Tamoxifen-inducible conditional knockout of Fgfr1, Fgfr2, Fgfr3 individually and combined in SPC+ cells, bleomycin injury model, flow cytometry, immunofluorescence","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific conditional knockout with defined survival/cellular phenotype and comparison to Fgfr3 knockout as control","pmids":["31860803"],"is_preprint":false},{"year":2017,"finding":"FGFR1 (not FGFR2) plays a more prominent role in primitive endoderm development and ESC exit from pluripotency. Loss of both FGFR1 and FGFR2 prevents PrE development; Fgfr2 expression becomes restricted to extraembryonic lineages including PrE in the blastocyst.","method":"Fluorescent reporter knockin lines, genetic double knockout in mouse embryos and ESCs","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double knockout genetic epistasis with reporter lines, single lab","pmids":["28552557"],"is_preprint":false},{"year":2021,"finding":"FGFR2 activation (S252W mutation) in the mammary gland drives triple-negative breast cancer with epithelial-mesenchymal transition regulated by FGFR2-STAT3 signaling. FGFR2 suppresses BRCA1 via the ERK-YY1 axis, and FGFR2 positively regulates PD-L1 expression.","method":"Mouse mammary gland-specific FGFR2-S252W knock-in model, BRCA1 knockout epistasis, phospho-STAT3/ERK immunoblotting, YY1/PD-L1 expression analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus mechanistic signaling pathway analysis, single lab","pmids":["34514747"],"is_preprint":false},{"year":2022,"finding":"FGFR2 signaling in ureteric epithelium enhances the SHH-BMP4 signaling axis: loss of Fgfr2 reduces epithelial Shh and mesenchymal Bmp4 expression; exogenous SHH or BMP4 rescues cellular defects of Fgfr2 mutant ureters, while SHH or BMP inhibition in wild-type ureters recapitulates the mutant phenotype.","method":"Ureteric epithelium-specific Fgfr2 conditional knockout, explant culture rescue with SHH/BMP4 agonists and antagonists, qPCR for Shh/Bmp4","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus bidirectional pharmacological epistasis in explant cultures with defined molecular and cellular readouts","pmids":["35020897"],"is_preprint":false},{"year":2022,"finding":"SOX9 transcriptionally activates FGF7 and FGFR2 expression in cholangiocarcinoma cells, and FGF7 promotes CCA proliferation via autocrine FGFR2 activation. WNT3A-TCF7-SOX9 axis induces pemigatinib resistance through (1) direct SOX9 promotion of FGFR2 transcription and (2) SOX9-elevated FGF7 secretion activating FGFR2 phosphorylation in an autocrine manner.","method":"mRNA sequencing, TCGA data analysis, TCF7 ChIP/luciferase reporter for SOX9, WNT3A stimulation, FGFR2/FGF7 siRNA, in vitro/in vivo validation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional reporter, siRNA, and in vivo validation, single lab","pmids":["35428876"],"is_preprint":false},{"year":2023,"finding":"FGFR2 mutations (common in endometrial cancer) enhance sensitivity to FGF7-mediated activation of ADAM17, which transactivates EGFR (shedding-dependent). FGFR2 mutants also trigger ADAM10-mediated Notch signaling in an ADAM17-dependent manner. FGFR2 mutants are not constitutively active but require FGF7 ligand stimulation to reprogram Notch and EGFR pathways.","method":"CRISPR/Cas9 loss-of-function, pharmacological inhibition, ectodomain shedding assays, luciferase Notch reporter, xenograft models, transcriptomic analysis of patient cohort","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted shedding assay, CRISPR KO, pharmacological approach, and in vivo xenograft, multiple orthogonal methods","pmids":["37165578"],"is_preprint":false},{"year":2021,"finding":"FGFR2 induces keratinocyte differentiation in esophageal squamous cell carcinoma through AKT but not MAPK signaling. FGFR2 knockdown induces EMT and enriches cancer stem cell populations; the IIIb isoform is specifically expressed in non-CSC/differentiated cells.","method":"shRNA knockdown, AKT/MAPK pathway inhibitors, EMT marker immunoblotting, flow cytometry for CSC markers in ESCC cell lines","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological dissection of AKT vs MAPK pathway, single lab","pmids":["34224333"],"is_preprint":false},{"year":2018,"finding":"CD151 post-transcriptionally regulates FGFR2 expression in breast cancer cells via PKC-dependent mechanisms involving the RNA-binding protein HuR and assembly of processing bodies (P-bodies); depletion of CD151 inhibits PKC and increases FGFR2 protein level.","method":"CD151 siRNA knockdown, PKC inhibition, HuR knockdown, P-body visualization, Western blotting, diacylglycerol lipid profiling","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular tools and pathway dissection, single lab","pmids":["30257985"],"is_preprint":false},{"year":2007,"finding":"FGFR2 promoter hypermethylation silences FGFR2 expression in gastric cancer cell lines; treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restores FGFR2 expression, demonstrating epigenetic regulation of FGFR2 via promoter methylation.","method":"Bisulfite sequencing/methylation analysis, 5-aza-2'-deoxycytidine treatment, RT-PCR/Western blot for FGFR2 re-expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation mapping plus pharmacological demethylation rescue, single lab","pmids":["17459342"],"is_preprint":false},{"year":2025,"finding":"FGFR2 inhibition induces necroptosis in esophageal squamous cell carcinoma via a RIP1/MLKL-dependent (RIP3-independent) pathway. MST1 is identified as a necroptotic component that interacts with RIP1 and MLKL and promotes necroptosis by phosphorylating MLKL at Thr216. FGFR2 inhibition also induces Ser518 phosphorylation of NF2, triggering its ubiquitin-mediated degradation, suppressing the Hippo pathway and activating YAP, which transcriptionally upregulates RIP1 and MLKL to amplify necroptosis.","method":"FGFR2 inhibitor treatment, RIP1/MLKL/RIP3 genetic knockdown, MST1 Co-IP with RIP1/MLKL, phospho-MLKL at Thr216 kinase assay, NF2 ubiquitination assay, YAP ChIP/transcriptional assay, humanized mouse xenografts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection of pathway components, kinase substrate assay, ubiquitination assay, in vivo validation, multiple orthogonal methods","pmids":["40319089"],"is_preprint":false},{"year":2019,"finding":"In cholangiocarcinoma, FGFR2 fusion proteins signal through the Ras-Erk pathway as a core downstream dependency, regardless of fusion partner identity or the V565F gatekeeper resistance mutation.","method":"CCA cell lines and patient-derived xenografts, MAPK/ERK phospho-immunoblotting, MEK inhibitor epistasis","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis in multiple cell and PDX models, single lab","pmids":["33741397"],"is_preprint":false},{"year":1992,"finding":"FGFR2 (bek and Cek3) isoforms generated by alternative splicing of the third immunoglobulin-like domain show distinct tissue-specific expression: bek (IIIb) is expressed in lung smooth muscle, while Cek3 (IIIc) is expressed predominantly in brain. Both isoforms are derived from the same pre-mRNA by alternative exon usage.","method":"Northern blot with isoform-specific probes, in situ hybridization, genomic analysis of exon proximity","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Northern blot and in situ hybridization with isoform-specific probes, single lab","pmids":["1419898"],"is_preprint":false}],"current_model":"FGFR2 is a transmembrane receptor tyrosine kinase that exists as tissue-specific alternatively spliced isoforms (IIIb/epithelial and IIIc/mesenchymal) regulated by ESRP1/2 RNA-binding proteins; upon FGF ligand binding (or constitutive activation by oncogenic mutations/fusions), the receptor autophosphorylates and signals through Ras-ERK, PI3K-AKT, PLCγ, and STAT3 pathways to control proliferation, differentiation, migration, and survival. Grb2 maintains a homeostatic non-signaling state by inhibiting both FGFR2 kinase and Shp2 phosphatase activity; Grb2 competes with PLCγ1 for a C-terminal receptor site, making basal invasiveness dependent on the Grb2/PLCγ1 ratio. Oncogenic gain-of-function mutations cause constitutive activation from both the cell surface and intracellular (ER) compartments, promote EMT via Sox2-Wnt/β-catenin suppression and ERK-YY1-BRCA1 axis, and in fused forms, dependence on the Ras-ERK pathway. PTPN9 dephosphorylates FGFR2 pY656/657 via an ACAP1-bridged complex. FGFR2 inhibition triggers RIP1/MLKL-dependent necroptosis via an MST1-NF2-YAP axis in squamous carcinoma cells."},"narrative":{"mechanistic_narrative":"FGFR2 is a transmembrane receptor tyrosine kinase that transduces FGF ligand signals into proliferation, differentiation, migration, and survival programs across epithelial development and oncogenesis [PMID:18552176, PMID:18594526]. Its functional output is shaped by mutually exclusive alternative splicing of its third immunoglobulin-like domain, producing tissue-restricted IIIb (epithelial) and IIIc (mesenchymal) isoforms generated from one pre-mRNA and controlled by the epithelial RNA-binding proteins ESRP1/2 [PMID:19285943, PMID:1419898]; the gene additionally generates secreted receptor forms lacking or retaining the kinase domain [PMID:1313574]. Isoform identity dictates ligand selectivity and biological role: FGF10 acts specifically through FGFR2-IIIb to drive pancreatic cancer invasion with induction of MT1-MMP and TGF-β1 [PMID:18594526], the IIIb isoform promotes keratinocyte differentiation via AKT in squamous carcinoma [PMID:34224333], and the IIIc isoform is required for male sex determination by repressing FOXL2 [PMID:28938467]. Receptor signaling homeostasis is governed by the adaptor Grb2, which simultaneously inhibits FGFR2 kinase and Shp2 phosphatase activity by direct binding; receptor-mediated phosphorylation of Grb2 releases this brake, and Grb2 competes with PLCγ1 for a C-terminal site so that the Grb2/PLCγ1 ratio sets basal phospholipase activity, calcium signaling, and invasiveness [PMID:23420874, PMID:24440983]. Downstream, FGFR2 engages Ras-ERK, PI3K-AKT, PLCγ, and STAT3 routes and can transactivate the EGFR/HER2/ErbB3 family, including c-Src–dependent HER2 transactivation conferring resistance to HER2-targeted therapy [PMID:18381441, PMID:31699826, PMID:34514747]. Through development FGFR2 is required for ureteric branching, where it acts via Frs2α-independent pathways and an SHH-BMP4 axis [PMID:21350013, PMID:35020897], and for alveolar type II cell survival after lung injury [PMID:31860803]. Oncogenic activation occurs through somatic kinase-activating mutations, amplification, and fusions: endometrial-cancer mutations are constitutively transforming [PMID:18552176], craniosynostosis mutant C278F signals from the ER through PLCγ and Frs2 in a ligand-independent manner [PMID:16844695], exon-18 truncation (FGFR2ΔE18) is a potent single driver [PMID:35948633], and fusion proteins are epistatically dependent on Ras-ERK regardless of partner or gatekeeper mutation [PMID:33741397]. FGFR2-driven tumors couple to EMT and immune evasion via Sox2-mediated Wnt suppression, an ERK-YY1-BRCA1 axis, STAT3, and PD-L1 upregulation [PMID:15781477, PMID:34514747], and FGFR2 expression is itself controlled by promoter methylation, the WNT3A-TCF7-SOX9 axis, and post-transcriptional CD151/PKC/HuR regulation [PMID:35428876, PMID:30257985, PMID:17459342]. Receptor phosphorylation is reversed by PTPN9 acting on pY656/657 through an ACAP1-bridged complex [PMID:37505213], and pharmacological FGFR2 inhibition triggers RIP1/MLKL-dependent necroptosis through an MST1-NF2-YAP axis in squamous carcinoma [PMID:40319089].","teleology":[{"year":1992,"claim":"Establishing that FGFR2 produces multiple receptor forms answered how a single gene could generate tissue-distinct receptor activities, defining the isoform repertoire that underlies its diverse biology.","evidence":"RNA blotting and cDNA cloning resolving full-length, secreted, and alternatively-spliced IgIII-domain isoforms (K-sam/bek/Cek3)","pmids":["1313574","1419898"],"confidence":"Medium","gaps":["Did not identify the splicing regulators controlling isoform choice","Functional consequences of secreted forms not tested"]},{"year":2005,"claim":"Linking activating FGFR2 mutations to Sox2-β-catenin repression of Wnt signaling explained how craniosynostosis mutations impair osteoblast differentiation, connecting receptor activation to a transcriptional differentiation block.","evidence":"Expression profiling, reporter assays, and Sox2–β-catenin Co-IP in osteoblasts with C342Y/S252W mutants","pmids":["15781477"],"confidence":"High","gaps":["Mechanism by which receptor activation induces Sox2 not defined","Relevance to non-skeletal contexts untested"]},{"year":2006,"claim":"Demonstrating that an under-glycosylated, ER-retained mutant FGFR2 still activates PLCγ and Frs2 revealed that the receptor can signal autonomously from intracellular compartments, expanding where FGFR2 signaling can originate.","evidence":"Glycosylation inhibition, subcellular fractionation, ubiquitination, and Frs2/PLCγ assays in osteoblastic cells","pmids":["16844695"],"confidence":"Medium","gaps":["Quantitative contribution of ER versus surface signaling unresolved","Single-lab biochemical evidence"]},{"year":2008,"claim":"Functional validation of endometrial somatic mutations and amplification-driven signaling established FGFR2 as an oncogenic driver and placed it upstream of the EGFR family, defining therapeutic targetability.","evidence":"NIH 3T3 transformation, kinase inhibition in mutant lines, and reciprocal phospho-immunoblotting/shRNA in amplified gastric lines","pmids":["18552176","18381441"],"confidence":"High","gaps":["Did not distinguish surface from intracellular activation","Cross-talk topology with EGFR family not structurally resolved"]},{"year":2008,"claim":"Showing FGF10 signals through FGFR2-IIIb to drive invasion with MT1-MMP/TGF-β1 induction tied isoform-specific ligand engagement to invasive output.","evidence":"Isoform-specific ligand stimulation, invasion assays, and downstream RT-PCR/ELISA in pancreatic cancer cells","pmids":["18594526"],"confidence":"Medium","gaps":["Direct signaling intermediates linking FGFR2-IIIb to MT1-MMP not mapped","Single-lab study"]},{"year":2009,"claim":"Identifying ESRP1/2 as the epithelial splicing regulators of the IIIb/IIIc switch answered how isoform choice is enforced in a cell-type-specific manner.","evidence":"cDNA screening with bidirectional ESRP overexpression and double-knockdown across cell lines","pmids":["19285943"],"confidence":"High","gaps":["Upstream control of ESRP expression not addressed","Did not test in vivo developmental contexts"]},{"year":2013,"claim":"Defining Grb2 as a dual inhibitor of FGFR2 kinase and Shp2 phosphatase established a homeostatic brake that keeps the receptor in a non-signaling resting state.","evidence":"In vitro kinase/phosphatase assays, FLIM-FRET, Co-IP, and mutagenesis","pmids":["23420874"],"confidence":"High","gaps":["In vivo physiological role of the brake untested","Stoichiometry under ligand stimulation not fully quantified"]},{"year":2014,"claim":"Showing PLCγ1 competes with Grb2 for a C-terminal site made basal invasiveness a function of the Grb2/PLCγ1 ratio, linking adaptor occupancy directly to motility.","evidence":"In vitro competition binding, NMR/biochemical site mapping, phospholipase and calcium assays, invasion assays","pmids":["24440983"],"confidence":"High","gaps":["Whether the ratio is regulated dynamically in tumors not shown","Other C-terminal SH3 competitors not surveyed"]},{"year":2017,"claim":"Genetic dissection in vivo separated FGFR2 isoform-specific developmental roles, showing FGFR2c is required for testis determination via FOXL2 repression and FGFR2-IIIb acts downstream of ΔNp63 in thymic development.","evidence":"Isoform-specific conditional knockouts with Foxl2 epistasis and p63 genetic complementation","pmids":["28938467","17626181"],"confidence":"High","gaps":["Signaling pathway from FGFR2c to FOXL2 not defined","Ligand sources in gonad/thymus not identified"]},{"year":2018,"claim":"Identifying NEGR1 as a physical partner that stabilizes surface FGFR2 and CD151 as a post-transcriptional regulator revealed mechanisms controlling FGFR2 protein abundance and signaling output.","evidence":"Co-IP and in vivo knockdown/rescue (NEGR1); siRNA, PKC inhibition, HuR/P-body analysis (CD151)","pmids":["30059965","30257985"],"confidence":"High","gaps":["Direct structural basis of NEGR1–FGFR2 interaction unknown","Whether CD151/HuR directly bind FGFR2 mRNA untested"]},{"year":2019,"claim":"Establishing that FGFR2 fusions depend on Ras-ERK and that stromal FGF5 drives FGFR2-mediated HER2 transactivation defined actionable resistance and dependency mechanisms in carcinoma.","evidence":"MEK inhibitor epistasis in CCA cell/PDX models; TAF co-culture, c-Src/HER2 phospho-immunoblotting, xenografts in breast cancer","pmids":["33741397","31699826"],"confidence":"Medium","gaps":["Fusion-partner-independent generality only partially surveyed","c-Src activation mechanism downstream of FGFR2 not fully resolved"]},{"year":2020,"claim":"Inducible AEC2-specific deletion showed FGFR2 is selectively required for alveolar type II cell survival after injury, defining a non-redundant homeostatic role distinct from other FGFRs.","evidence":"Tamoxifen-inducible cell-type-specific knockouts of Fgfr1/2/3 with bleomycin injury and flow cytometry","pmids":["31860803"],"confidence":"High","gaps":["Downstream survival effectors in AEC2s not identified","Ligand driving the survival signal not defined"]},{"year":2021,"claim":"Pathway dissection connected FGFR2 to EMT, BRCA1 suppression, and PD-L1 in breast cancer and to AKT-driven differentiation in squamous carcinoma, mapping how FGFR2 signaling output diverges by context.","evidence":"S252W mammary knock-in with STAT3/ERK-YY1-BRCA1 analysis; shRNA and AKT/MAPK inhibitor dissection in ESCC","pmids":["34514747","34224333"],"confidence":"Medium","gaps":["How the same receptor selects AKT versus MAPK outputs unresolved","Direct YY1–BRCA1 promoter mechanism not fully established"]},{"year":2022,"claim":"An in vivo screen identified FGFR2ΔE18 as a potent single-driver alteration and ureteric studies placed FGFR2 within a Frs2α-independent SHH-BMP4 developmental axis, refining which alterations and pathways are functionally decisive.","evidence":"Transposon in vivo screen and variant compendium (ΔE18); conditional knockouts with SHH/BMP4 rescue in ureteric explants; WNT3A-TCF7-SOX9 reporter analysis in CCA","pmids":["35948633","35020897","35428876"],"confidence":"High","gaps":["Mechanism by which ΔE18 truncation activates the receptor not detailed","Link between FGFR2 and Shh transcription not defined"]},{"year":2023,"claim":"Identifying PTPN9 as the phosphatase reversing FGFR2 pY656/657 and showing some FGFR2 mutants require FGF7 to reprogram ADAM-mediated EGFR/Notch signaling refined the regulation and ligand-dependence of mutant receptor signaling.","evidence":"Phosphatase assays with ACAP1-bridged Co-IP and structural modeling (PTPN9); CRISPR KO, shedding assays, Notch reporters, xenografts (ADAM17/10)","pmids":["37505213","37165578"],"confidence":"High","gaps":["Whether all oncogenic 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Ectopic expression of either ESRP in IIIc-expressing cells switches endogenous FGFR2 splicing to the IIIb isoform; knockdown of both ESRPs in IIIb-expressing cells switches splicing to IIIc.\",\n      \"method\": \"cDNA expression screening, ectopic overexpression, RNAi knockdown in cell lines\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional gain- and loss-of-function experiments, replicated across multiple cell lines\",\n      \"pmids\": [\"19285943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Somatic FGFR2 mutations found in endometrial carcinoma are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells; inhibition of FGFR2 kinase activity in endometrial cancer cell lines bearing these mutations inhibits transformation and survival.\",\n      \"method\": \"NIH 3T3 transformation assay, small-molecule kinase inhibition in mutant cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional transformation assay plus selective pharmacological inhibition with defined cellular phenotype\",\n      \"pmids\": [\"18552176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In FGFR2-amplified gastric cancer cell lines, FGFR2 is constitutively tyrosine-phosphorylated and drives phosphorylation of EGFR family members (EGFR, HER2, ErbB3). FGFR2 kinase inhibition abolishes EGFR/HER2/ErbB3 phosphorylation, placing FGFR2 upstream of the EGFR pathway. shRNA to ErbB3 confirms a functional role for this downstream activation in proliferation.\",\n      \"method\": \"FGFR2-selective small-molecule inhibitor, shRNA knockdown, phosphotyrosine immunoblotting in amplified cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic (shRNA) approaches, reciprocal phospho-immunoblotting establishing upstream-downstream order\",\n      \"pmids\": [\"18381441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Activating FGFR2 mutations (C342Y or S252W) and exogenous FGF in osteoblasts induce Sox2 expression, which associates with β-catenin and inhibits Wnt-responsive transcription through its C-terminal domain, thereby suppressing Wnt target gene expression and osteoblast differentiation.\",\n      \"method\": \"Gene expression profiling, constitutive Sox2 expression, reporter assay, co-immunoprecipitation of Sox2–β-catenin\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (expression profiling, reporter assay, Co-IP, in vivo expression), single lab but rigorous\",\n      \"pmids\": [\"15781477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The adaptor protein Grb2 controls FGFR2 phosphorylation homeostasis by simultaneously inhibiting FGFR2 kinase activity and Shp2 phosphatase activity through direct receptor binding. FGFR2 phosphorylates Grb2, releasing it from the receptor and allowing both FGFR2 kinase and Shp2 phosphatase activity to increase; Shp2 dephosphorylates Grb2 to restore the inhibitory complex.\",\n      \"method\": \"In vitro kinase/phosphatase assays, FLIM-FRET, Co-IP, mutagenesis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assays combined with FRET-based live-cell measurements and mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23420874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In non-stimulated FGFR2-expressing cancer cells, the SH3 domain of PLCγ1 directly competes with the C-terminal SH3 domain of Grb2 for a phosphorylation-independent binding site at the very C-terminus of FGFR2. Reduced Grb2 concentration permits PLCγ1 recruitment, upregulating basal phospholipase C activity, PIP2 turnover, intracellular calcium, cell motility, and invasion.\",\n      \"method\": \"In vitro binding competition assay, NMR/biochemical mapping of binding site, phospholipase activity assay, calcium imaging, invasion assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of competition, structural mapping, and functional cellular readouts in a single study\",\n      \"pmids\": [\"24440983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The craniosynostosis mutation FGFR2-C278F results in diminished N-linked glycosylation, increased proteasomal/lysosomal degradation, and restricted subcellular localization (ER retention). Both the C278F mutant and unglycosylated wild-type FGFR2 activate PLCγ and show increased binding to Frs2 in a ligand-independent manner from intracellular compartments, demonstrating that autoactive FGFR2 can signal from the ER.\",\n      \"method\": \"Glycosylation inhibition, subcellular fractionation, ubiquitination assay, PLCγ phosphorylation assay, Frs2 co-immunoprecipitation in osteoblastic cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (glycosylation, fractionation, Co-IP, signaling assays) in a single lab\",\n      \"pmids\": [\"16844695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The K-sam (FGFR2) gene expresses at least four classes of mRNA encoding: (1) a full-length transmembrane receptor tyrosine kinase, (2) a secreted receptor retaining the tyrosine kinase domain, and (3) a secreted receptor lacking the tyrosine kinase domain, demonstrating that FGFR2 produces both membrane-bound and secreted receptor forms.\",\n      \"method\": \"RNA blot analysis with multiple probes, cDNA isolation and sequencing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA cloning and sequencing with Northern blot validation, single lab\",\n      \"pmids\": [\"1313574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FGF10 induces migration and invasion of pancreatic cancer cells specifically through interaction with the FGFR2-IIIb isoform, and concurrently induces expression of MT1-MMP mRNA and TGF-β1 mRNA and increased TGF-β1 secretion.\",\n      \"method\": \"Migration/invasion assays with recombinant FGF10, isoform-specific receptor identification, RT-PCR for MT1-MMP and TGF-β1, ELISA for TGF-β1 protein\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with ligand stimulation plus downstream gene expression, isoform specificity established, single lab\",\n      \"pmids\": [\"18594526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NEGR1 physically interacts with FGFR2, decreases FGFR2 degradation from the plasma membrane, and modulates FGFR2-dependent ERK and AKT signaling. NEGR1 knockdown reduces spine density and neuronal migration similarly to FGFR2 knockdown; FGFR2 overexpression rescues all defects caused by NEGR1 knockdown in vivo, placing NEGR1 upstream of FGFR2.\",\n      \"method\": \"Co-immunoprecipitation, in vivo cortical electroporation knockdown/rescue, Western blotting for p-ERK and p-AKT, FGFR2 surface degradation assay\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus in vivo epistasis rescue experiment with multiple signaling readouts\",\n      \"pmids\": [\"30059965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Truncation of FGFR2 exon 18 (FGFR2ΔE18), generated by diverse structural alterations (rearrangements, partial amplifications, nonsense/frameshift mutations), is a potent single-driver oncogenic mutation; full-length FGFR2 amplification requires cooperating driver genes for oncogenic competence. FGFR2ΔE18 variants are sensitive to FGFR-targeted therapy in mouse and human tumor models.\",\n      \"method\": \"Transposon-based in vivo screen, tumor modelling in mice, in vitro functional compendium of FGFR2 variants, preclinical xenograft models, clinical trial correlation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic screen plus multi-model functional validation and clinical correlation\",\n      \"pmids\": [\"35948633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tumor-associated fibroblasts produce FGF5, which activates FGFR2 in breast cancer cells; FGFR2 then transactivates HER2 via c-Src, causing resistance to HER2-targeted therapies. FGFR2 inhibition abrogates this pathway and re-sensitizes resistant cells to HER2 therapy in vitro and in vivo.\",\n      \"method\": \"Co-culture of TAFs and cancer cells, FGFR2 inhibitor treatment, shRNA knockdown, phospho-immunoblotting for c-Src and HER2, mouse xenograft co-injection\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with in vitro and in vivo confirmation, single lab\",\n      \"pmids\": [\"31699826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids toward cholangiocarcinoma on a Tp53-/- background via Ras-Erk signaling. Dual FGFR2 inhibition + MEK1/2 inhibition is more effective than single-agent FGFR inhibition in vitro and in vivo, demonstrating epistatic dependence of FGFR2 fusions on Ras-ERK signaling.\",\n      \"method\": \"Liver organoid transduction, mouse transplantation, MEK inhibitor combination experiments, in vitro and in vivo pharmacology\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (organoid/transplant model) plus pharmacological epistasis, in vitro and in vivo, multiple fusion variants tested\",\n      \"pmids\": [\"33741397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGFR2c isoform (not FGFR2b) is specifically required for male sex determination in mice. XY Fgfr2c-/- gonads show complete male-to-female sex reversal with ectopic FOXL2 expression; ablation of Foxl2 partially rescues sex reversal, placing FGFR2c upstream of FOXL2 repression in testis determination.\",\n      \"method\": \"Conditional Fgfr2c knockout mice, genetic epistasis with Foxl2 knockout, immunofluorescence for SOX9/FOXL2 markers\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific conditional knockout plus Foxl2 epistasis rescue experiment with clear molecular readouts\",\n      \"pmids\": [\"28938467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DeltaNp63 directly regulates FGFR2-IIIb expression in thymic epithelial cells via interaction with APOBEC1-binding protein 1; FGFR2-IIIb knockout mice show thymic defects similar to p63-/- mice, placing FGFR2-IIIb as a downstream effector of DeltaNp63 in thymic development.\",\n      \"method\": \"p63-/- mouse genetic complementation with TAp63 or DeltaNp63 transgenes, Fgfr2-IIIb knockout mice, chromatin interaction analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation epistasis plus knockout phenotype comparison, single lab\",\n      \"pmids\": [\"17626181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTPN9 directly dephosphorylates FGFR2 at pY656/657. PTPN9 interacts with FGFR2 via ACAP1 mediation; the sec14p domain of PTPN9 binds FGFR2 through ACAP1's PH and Arf-GAP domains. Key amino acids (YRETRRKE motif, Y471 of PTPN9) are required for the interaction. PTPN9 overexpression synergistically enhances pemigatinib effectiveness in CCA models including PDX.\",\n      \"method\": \"Phosphatase activity assay, FGFR2-PTPN9 structural modeling, Co-IP, mutagenesis of interaction sites, in vitro and PDX pharmacology\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phosphatase substrate assay, structural modeling, mutagenesis, and in vivo PDX, single lab\",\n      \"pmids\": [\"37505213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Conditional deletion of Fgfr2 in the ureteric bud causes severe ureteric branching defects. Combining Fgfr2 deletion with Frs2α deletion produces more severe defects than either single knockout at later stages, but is equivalent to Fgfr2 deletion alone at E13.5. Point mutations in the Frs2α binding site of Fgfr2 do not phenocopy Fgfr2 deletion, indicating that Fgfr2 acts via Frs2α-independent pathways in the ureteric epithelium.\",\n      \"method\": \"Conditional knockout mice (Hoxb7-Cre), compound Fgfr2/Frs2α knockout, point mutation knock-in (Fgfr2LR/LR), 3D ureteric reconstruction\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic models with clear morphological phenotype comparison, single lab\",\n      \"pmids\": [\"21350013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Inducible inactivation of Fgfr2 (but not Fgfr3) specifically in SPC+ type II alveolar epithelial cells causes increased mortality and lung injury after bleomycin administration and loss of AEC2s, demonstrating that AEC2-specific FGFR2 signaling is required for AEC2 survival and homeostasis after lung injury.\",\n      \"method\": \"Tamoxifen-inducible conditional knockout of Fgfr1, Fgfr2, Fgfr3 individually and combined in SPC+ cells, bleomycin injury model, flow cytometry, immunofluorescence\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific conditional knockout with defined survival/cellular phenotype and comparison to Fgfr3 knockout as control\",\n      \"pmids\": [\"31860803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGFR1 (not FGFR2) plays a more prominent role in primitive endoderm development and ESC exit from pluripotency. Loss of both FGFR1 and FGFR2 prevents PrE development; Fgfr2 expression becomes restricted to extraembryonic lineages including PrE in the blastocyst.\",\n      \"method\": \"Fluorescent reporter knockin lines, genetic double knockout in mouse embryos and ESCs\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double knockout genetic epistasis with reporter lines, single lab\",\n      \"pmids\": [\"28552557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGFR2 activation (S252W mutation) in the mammary gland drives triple-negative breast cancer with epithelial-mesenchymal transition regulated by FGFR2-STAT3 signaling. FGFR2 suppresses BRCA1 via the ERK-YY1 axis, and FGFR2 positively regulates PD-L1 expression.\",\n      \"method\": \"Mouse mammary gland-specific FGFR2-S252W knock-in model, BRCA1 knockout epistasis, phospho-STAT3/ERK immunoblotting, YY1/PD-L1 expression analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus mechanistic signaling pathway analysis, single lab\",\n      \"pmids\": [\"34514747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FGFR2 signaling in ureteric epithelium enhances the SHH-BMP4 signaling axis: loss of Fgfr2 reduces epithelial Shh and mesenchymal Bmp4 expression; exogenous SHH or BMP4 rescues cellular defects of Fgfr2 mutant ureters, while SHH or BMP inhibition in wild-type ureters recapitulates the mutant phenotype.\",\n      \"method\": \"Ureteric epithelium-specific Fgfr2 conditional knockout, explant culture rescue with SHH/BMP4 agonists and antagonists, qPCR for Shh/Bmp4\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus bidirectional pharmacological epistasis in explant cultures with defined molecular and cellular readouts\",\n      \"pmids\": [\"35020897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX9 transcriptionally activates FGF7 and FGFR2 expression in cholangiocarcinoma cells, and FGF7 promotes CCA proliferation via autocrine FGFR2 activation. WNT3A-TCF7-SOX9 axis induces pemigatinib resistance through (1) direct SOX9 promotion of FGFR2 transcription and (2) SOX9-elevated FGF7 secretion activating FGFR2 phosphorylation in an autocrine manner.\",\n      \"method\": \"mRNA sequencing, TCGA data analysis, TCF7 ChIP/luciferase reporter for SOX9, WNT3A stimulation, FGFR2/FGF7 siRNA, in vitro/in vivo validation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional reporter, siRNA, and in vivo validation, single lab\",\n      \"pmids\": [\"35428876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FGFR2 mutations (common in endometrial cancer) enhance sensitivity to FGF7-mediated activation of ADAM17, which transactivates EGFR (shedding-dependent). FGFR2 mutants also trigger ADAM10-mediated Notch signaling in an ADAM17-dependent manner. FGFR2 mutants are not constitutively active but require FGF7 ligand stimulation to reprogram Notch and EGFR pathways.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function, pharmacological inhibition, ectodomain shedding assays, luciferase Notch reporter, xenograft models, transcriptomic analysis of patient cohort\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted shedding assay, CRISPR KO, pharmacological approach, and in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"37165578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGFR2 induces keratinocyte differentiation in esophageal squamous cell carcinoma through AKT but not MAPK signaling. FGFR2 knockdown induces EMT and enriches cancer stem cell populations; the IIIb isoform is specifically expressed in non-CSC/differentiated cells.\",\n      \"method\": \"shRNA knockdown, AKT/MAPK pathway inhibitors, EMT marker immunoblotting, flow cytometry for CSC markers in ESCC cell lines\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological dissection of AKT vs MAPK pathway, single lab\",\n      \"pmids\": [\"34224333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD151 post-transcriptionally regulates FGFR2 expression in breast cancer cells via PKC-dependent mechanisms involving the RNA-binding protein HuR and assembly of processing bodies (P-bodies); depletion of CD151 inhibits PKC and increases FGFR2 protein level.\",\n      \"method\": \"CD151 siRNA knockdown, PKC inhibition, HuR knockdown, P-body visualization, Western blotting, diacylglycerol lipid profiling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular tools and pathway dissection, single lab\",\n      \"pmids\": [\"30257985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FGFR2 promoter hypermethylation silences FGFR2 expression in gastric cancer cell lines; treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restores FGFR2 expression, demonstrating epigenetic regulation of FGFR2 via promoter methylation.\",\n      \"method\": \"Bisulfite sequencing/methylation analysis, 5-aza-2'-deoxycytidine treatment, RT-PCR/Western blot for FGFR2 re-expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation mapping plus pharmacological demethylation rescue, single lab\",\n      \"pmids\": [\"17459342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGFR2 inhibition induces necroptosis in esophageal squamous cell carcinoma via a RIP1/MLKL-dependent (RIP3-independent) pathway. MST1 is identified as a necroptotic component that interacts with RIP1 and MLKL and promotes necroptosis by phosphorylating MLKL at Thr216. FGFR2 inhibition also induces Ser518 phosphorylation of NF2, triggering its ubiquitin-mediated degradation, suppressing the Hippo pathway and activating YAP, which transcriptionally upregulates RIP1 and MLKL to amplify necroptosis.\",\n      \"method\": \"FGFR2 inhibitor treatment, RIP1/MLKL/RIP3 genetic knockdown, MST1 Co-IP with RIP1/MLKL, phospho-MLKL at Thr216 kinase assay, NF2 ubiquitination assay, YAP ChIP/transcriptional assay, humanized mouse xenografts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection of pathway components, kinase substrate assay, ubiquitination assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"40319089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In cholangiocarcinoma, FGFR2 fusion proteins signal through the Ras-Erk pathway as a core downstream dependency, regardless of fusion partner identity or the V565F gatekeeper resistance mutation.\",\n      \"method\": \"CCA cell lines and patient-derived xenografts, MAPK/ERK phospho-immunoblotting, MEK inhibitor epistasis\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis in multiple cell and PDX models, single lab\",\n      \"pmids\": [\"33741397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"FGFR2 (bek and Cek3) isoforms generated by alternative splicing of the third immunoglobulin-like domain show distinct tissue-specific expression: bek (IIIb) is expressed in lung smooth muscle, while Cek3 (IIIc) is expressed predominantly in brain. Both isoforms are derived from the same pre-mRNA by alternative exon usage.\",\n      \"method\": \"Northern blot with isoform-specific probes, in situ hybridization, genomic analysis of exon proximity\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Northern blot and in situ hybridization with isoform-specific probes, single lab\",\n      \"pmids\": [\"1419898\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGFR2 is a transmembrane receptor tyrosine kinase that exists as tissue-specific alternatively spliced isoforms (IIIb/epithelial and IIIc/mesenchymal) regulated by ESRP1/2 RNA-binding proteins; upon FGF ligand binding (or constitutive activation by oncogenic mutations/fusions), the receptor autophosphorylates and signals through Ras-ERK, PI3K-AKT, PLCγ, and STAT3 pathways to control proliferation, differentiation, migration, and survival. Grb2 maintains a homeostatic non-signaling state by inhibiting both FGFR2 kinase and Shp2 phosphatase activity; Grb2 competes with PLCγ1 for a C-terminal receptor site, making basal invasiveness dependent on the Grb2/PLCγ1 ratio. Oncogenic gain-of-function mutations cause constitutive activation from both the cell surface and intracellular (ER) compartments, promote EMT via Sox2-Wnt/β-catenin suppression and ERK-YY1-BRCA1 axis, and in fused forms, dependence on the Ras-ERK pathway. PTPN9 dephosphorylates FGFR2 pY656/657 via an ACAP1-bridged complex. FGFR2 inhibition triggers RIP1/MLKL-dependent necroptosis via an MST1-NF2-YAP axis in squamous carcinoma cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGFR2 is a transmembrane receptor tyrosine kinase that transduces FGF ligand signals into proliferation, differentiation, migration, and survival programs across epithelial development and oncogenesis [#1, #8]. Its functional output is shaped by mutually exclusive alternative splicing of its third immunoglobulin-like domain, producing tissue-restricted IIIb (epithelial) and IIIc (mesenchymal) isoforms generated from one pre-mRNA and controlled by the epithelial RNA-binding proteins ESRP1/2 [#0, #28]; the gene additionally generates secreted receptor forms lacking or retaining the kinase domain [#7]. Isoform identity dictates ligand selectivity and biological role: FGF10 acts specifically through FGFR2-IIIb to drive pancreatic cancer invasion with induction of MT1-MMP and TGF-\\u03b21 [#8], the IIIb isoform promotes keratinocyte differentiation via AKT in squamous carcinoma [#23], and the IIIc isoform is required for male sex determination by repressing FOXL2 [#13]. Receptor signaling homeostasis is governed by the adaptor Grb2, which simultaneously inhibits FGFR2 kinase and Shp2 phosphatase activity by direct binding; receptor-mediated phosphorylation of Grb2 releases this brake, and Grb2 competes with PLC\\u03b31 for a C-terminal site so that the Grb2/PLC\\u03b31 ratio sets basal phospholipase activity, calcium signaling, and invasiveness [#4, #5]. Downstream, FGFR2 engages Ras-ERK, PI3K-AKT, PLC\\u03b3, and STAT3 routes and can transactivate the EGFR/HER2/ErbB3 family, including c-Src\\u2013dependent HER2 transactivation conferring resistance to HER2-targeted therapy [#2, #11, #19]. Through development FGFR2 is required for ureteric branching, where it acts via Frs2\\u03b1-independent pathways and an SHH-BMP4 axis [#16, #20], and for alveolar type II cell survival after lung injury [#17]. Oncogenic activation occurs through somatic kinase-activating mutations, amplification, and fusions: endometrial-cancer mutations are constitutively transforming [#1], craniosynostosis mutant C278F signals from the ER through PLC\\u03b3 and Frs2 in a ligand-independent manner [#6], exon-18 truncation (FGFR2\\u0394E18) is a potent single driver [#10], and fusion proteins are epistatically dependent on Ras-ERK regardless of partner or gatekeeper mutation [#12, #27]. FGFR2-driven tumors couple to EMT and immune evasion via Sox2-mediated Wnt suppression, an ERK-YY1-BRCA1 axis, STAT3, and PD-L1 upregulation [#3, #19], and FGFR2 expression is itself controlled by promoter methylation, the WNT3A-TCF7-SOX9 axis, and post-transcriptional CD151/PKC/HuR regulation [#21, #24, #25]. Receptor phosphorylation is reversed by PTPN9 acting on pY656/657 through an ACAP1-bridged complex [#15], and pharmacological FGFR2 inhibition triggers RIP1/MLKL-dependent necroptosis through an MST1-NF2-YAP axis in squamous carcinoma [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing that FGFR2 produces multiple receptor forms answered how a single gene could generate tissue-distinct receptor activities, defining the isoform repertoire that underlies its diverse biology.\",\n      \"evidence\": \"RNA blotting and cDNA cloning resolving full-length, secreted, and alternatively-spliced IgIII-domain isoforms (K-sam/bek/Cek3)\",\n      \"pmids\": [\"1313574\", \"1419898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the splicing regulators controlling isoform choice\", \"Functional consequences of secreted forms not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking activating FGFR2 mutations to Sox2-\\u03b2-catenin repression of Wnt signaling explained how craniosynostosis mutations impair osteoblast differentiation, connecting receptor activation to a transcriptional differentiation block.\",\n      \"evidence\": \"Expression profiling, reporter assays, and Sox2\\u2013\\u03b2-catenin Co-IP in osteoblasts with C342Y/S252W mutants\",\n      \"pmids\": [\"15781477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which receptor activation induces Sox2 not defined\", \"Relevance to non-skeletal contexts untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that an under-glycosylated, ER-retained mutant FGFR2 still activates PLC\\u03b3 and Frs2 revealed that the receptor can signal autonomously from intracellular compartments, expanding where FGFR2 signaling can originate.\",\n      \"evidence\": \"Glycosylation inhibition, subcellular fractionation, ubiquitination, and Frs2/PLC\\u03b3 assays in osteoblastic cells\",\n      \"pmids\": [\"16844695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of ER versus surface signaling unresolved\", \"Single-lab biochemical evidence\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Functional validation of endometrial somatic mutations and amplification-driven signaling established FGFR2 as an oncogenic driver and placed it upstream of the EGFR family, defining therapeutic targetability.\",\n      \"evidence\": \"NIH 3T3 transformation, kinase inhibition in mutant lines, and reciprocal phospho-immunoblotting/shRNA in amplified gastric lines\",\n      \"pmids\": [\"18552176\", \"18381441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish surface from intracellular activation\", \"Cross-talk topology with EGFR family not structurally resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing FGF10 signals through FGFR2-IIIb to drive invasion with MT1-MMP/TGF-\\u03b21 induction tied isoform-specific ligand engagement to invasive output.\",\n      \"evidence\": \"Isoform-specific ligand stimulation, invasion assays, and downstream RT-PCR/ELISA in pancreatic cancer cells\",\n      \"pmids\": [\"18594526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct signaling intermediates linking FGFR2-IIIb to MT1-MMP not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying ESRP1/2 as the epithelial splicing regulators of the IIIb/IIIc switch answered how isoform choice is enforced in a cell-type-specific manner.\",\n      \"evidence\": \"cDNA screening with bidirectional ESRP overexpression and double-knockdown across cell lines\",\n      \"pmids\": [\"19285943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream control of ESRP expression not addressed\", \"Did not test in vivo developmental contexts\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining Grb2 as a dual inhibitor of FGFR2 kinase and Shp2 phosphatase established a homeostatic brake that keeps the receptor in a non-signaling resting state.\",\n      \"evidence\": \"In vitro kinase/phosphatase assays, FLIM-FRET, Co-IP, and mutagenesis\",\n      \"pmids\": [\"23420874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological role of the brake untested\", \"Stoichiometry under ligand stimulation not fully quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing PLC\\u03b31 competes with Grb2 for a C-terminal site made basal invasiveness a function of the Grb2/PLC\\u03b31 ratio, linking adaptor occupancy directly to motility.\",\n      \"evidence\": \"In vitro competition binding, NMR/biochemical site mapping, phospholipase and calcium assays, invasion assays\",\n      \"pmids\": [\"24440983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the ratio is regulated dynamically in tumors not shown\", \"Other C-terminal SH3 competitors not surveyed\"]\n    },\n    {\n      \"year\": \"2017\",\n      \"claim\": \"Genetic dissection in vivo separated FGFR2 isoform-specific developmental roles, showing FGFR2c is required for testis determination via FOXL2 repression and FGFR2-IIIb acts downstream of \\u0394Np63 in thymic development.\",\n      \"evidence\": \"Isoform-specific conditional knockouts with Foxl2 epistasis and p63 genetic complementation\",\n      \"pmids\": [\"28938467\", \"17626181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from FGFR2c to FOXL2 not defined\", \"Ligand sources in gonad/thymus not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying NEGR1 as a physical partner that stabilizes surface FGFR2 and CD151 as a post-transcriptional regulator revealed mechanisms controlling FGFR2 protein abundance and signaling output.\",\n      \"evidence\": \"Co-IP and in vivo knockdown/rescue (NEGR1); siRNA, PKC inhibition, HuR/P-body analysis (CD151)\",\n      \"pmids\": [\"30059965\", \"30257985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of NEGR1\\u2013FGFR2 interaction unknown\", \"Whether CD151/HuR directly bind FGFR2 mRNA untested\"]\n    },\n    {\n      \"year\": \"2019\",\n      \"claim\": \"Establishing that FGFR2 fusions depend on Ras-ERK and that stromal FGF5 drives FGFR2-mediated HER2 transactivation defined actionable resistance and dependency mechanisms in carcinoma.\",\n      \"evidence\": \"MEK inhibitor epistasis in CCA cell/PDX models; TAF co-culture, c-Src/HER2 phospho-immunoblotting, xenografts in breast cancer\",\n      \"pmids\": [\"33741397\", \"31699826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fusion-partner-independent generality only partially surveyed\", \"c-Src activation mechanism downstream of FGFR2 not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Inducible AEC2-specific deletion showed FGFR2 is selectively required for alveolar type II cell survival after injury, defining a non-redundant homeostatic role distinct from other FGFRs.\",\n      \"evidence\": \"Tamoxifen-inducible cell-type-specific knockouts of Fgfr1/2/3 with bleomycin injury and flow cytometry\",\n      \"pmids\": [\"31860803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream survival effectors in AEC2s not identified\", \"Ligand driving the survival signal not defined\"]\n    },\n    {\n      \"year\": \"2021\",\n      \"claim\": \"Pathway dissection connected FGFR2 to EMT, BRCA1 suppression, and PD-L1 in breast cancer and to AKT-driven differentiation in squamous carcinoma, mapping how FGFR2 signaling output diverges by context.\",\n      \"evidence\": \"S252W mammary knock-in with STAT3/ERK-YY1-BRCA1 analysis; shRNA and AKT/MAPK inhibitor dissection in ESCC\",\n      \"pmids\": [\"34514747\", \"34224333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the same receptor selects AKT versus MAPK outputs unresolved\", \"Direct YY1\\u2013BRCA1 promoter mechanism not fully established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An in vivo screen identified FGFR2\\u0394E18 as a potent single-driver alteration and ureteric studies placed FGFR2 within a Frs2\\u03b1-independent SHH-BMP4 developmental axis, refining which alterations and pathways are functionally decisive.\",\n      \"evidence\": \"Transposon in vivo screen and variant compendium (\\u0394E18); conditional knockouts with SHH/BMP4 rescue in ureteric explants; WNT3A-TCF7-SOX9 reporter analysis in CCA\",\n      \"pmids\": [\"35948633\", \"35020897\", \"35428876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which \\u0394E18 truncation activates the receptor not detailed\", \"Link between FGFR2 and Shh transcription not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying PTPN9 as the phosphatase reversing FGFR2 pY656/657 and showing some FGFR2 mutants require FGF7 to reprogram ADAM-mediated EGFR/Notch signaling refined the regulation and ligand-dependence of mutant receptor signaling.\",\n      \"evidence\": \"Phosphatase assays with ACAP1-bridged Co-IP and structural modeling (PTPN9); CRISPR KO, shedding assays, Notch reporters, xenografts (ADAM17/10)\",\n      \"pmids\": [\"37505213\", \"37165578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all oncogenic mutants are ligand-dependent versus constitutive remains heterogeneous\", \"Structural model of PTPN9\\u2013ACAP1\\u2013FGFR2 not experimentally solved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining an MST1-NF2-YAP necroptotic response to FGFR2 inhibition revealed a programmed cell-death vulnerability engaged when the receptor is pharmacologically blocked.\",\n      \"evidence\": \"FGFR2 inhibitor with RIP1/MLKL/RIP3 knockdown, MST1 Co-IP, phospho-MLKL kinase assay, NF2 ubiquitination, YAP ChIP, and humanized xenografts\",\n      \"pmids\": [\"40319089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why this pathway is RIP3-independent mechanistically unclear\", \"Generality beyond squamous carcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the receptor's spatial origin (surface versus ER), isoform identity, and adaptor occupancy are integrated to select among Ras-ERK, AKT, PLC\\u03b3, and STAT3 outputs in a given cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking isoform/compartment to specific downstream pathway choice\", \"Quantitative rules governing ligand-dependent versus constitutive mutant signaling not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 4, 6]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 8, 17]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 12, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 10, 12, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 16, 17, 20]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 28, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRB2\", \"PLCG1\", \"FRS2\", \"PTPN9\", \"ACAP1\", \"NEGR1\", \"SHP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}