Affinage

FGFR2

Fibroblast growth factor receptor 2 · UniProt P21802

Length
821 aa
Mass
92.0 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 Medium

    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)

    PMID:1313574 PMID:1419898

    Open questions at the time
    • Did not identify the splicing regulators controlling isoform choice
    • Functional consequences of secreted forms not tested
  2. 2005 High

    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

    PMID:15781477

    Open questions at the time
    • Mechanism by which receptor activation induces Sox2 not defined
    • Relevance to non-skeletal contexts untested
  3. 2006 Medium

    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

    PMID:16844695

    Open questions at the time
    • Quantitative contribution of ER versus surface signaling unresolved
    • Single-lab biochemical evidence
  4. 2008 High

    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

    PMID:18381441 PMID:18552176

    Open questions at the time
    • Did not distinguish surface from intracellular activation
    • Cross-talk topology with EGFR family not structurally resolved
  5. 2008 Medium

    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

    PMID:18594526

    Open questions at the time
    • Direct signaling intermediates linking FGFR2-IIIb to MT1-MMP not mapped
    • Single-lab study
  6. 2009 High

    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

    PMID:19285943

    Open questions at the time
    • Upstream control of ESRP expression not addressed
    • Did not test in vivo developmental contexts
  7. 2013 High

    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

    PMID:23420874

    Open questions at the time
    • In vivo physiological role of the brake untested
    • Stoichiometry under ligand stimulation not fully quantified
  8. 2014 High

    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

    PMID:24440983

    Open questions at the time
    • Whether the ratio is regulated dynamically in tumors not shown
    • Other C-terminal SH3 competitors not surveyed
  9. 2017 High

    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

    PMID:17626181 PMID:28938467

    Open questions at the time
    • Signaling pathway from FGFR2c to FOXL2 not defined
    • Ligand sources in gonad/thymus not identified
  10. 2018 High

    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)

    PMID:30059965 PMID:30257985

    Open questions at the time
    • Direct structural basis of NEGR1–FGFR2 interaction unknown
    • Whether CD151/HuR directly bind FGFR2 mRNA untested
  11. 2019 Medium

    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

    PMID:31699826 PMID:33741397

    Open questions at the time
    • Fusion-partner-independent generality only partially surveyed
    • c-Src activation mechanism downstream of FGFR2 not fully resolved
  12. 2020 High

    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

    PMID:31860803

    Open questions at the time
    • Downstream survival effectors in AEC2s not identified
    • Ligand driving the survival signal not defined
  13. 2021 Medium

    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

    PMID:34224333 PMID:34514747

    Open questions at the time
    • How the same receptor selects AKT versus MAPK outputs unresolved
    • Direct YY1–BRCA1 promoter mechanism not fully established
  14. 2022 High

    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

    PMID:35020897 PMID:35428876 PMID:35948633

    Open questions at the time
    • Mechanism by which ΔE18 truncation activates the receptor not detailed
    • Link between FGFR2 and Shh transcription not defined
  15. 2023 High

    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)

    PMID:37165578 PMID:37505213

    Open questions at the time
    • Whether all oncogenic mutants are ligand-dependent versus constitutive remains heterogeneous
    • Structural model of PTPN9–ACAP1–FGFR2 not experimentally solved
  16. 2025 High

    Defining an MST1-NF2-YAP necroptotic response to FGFR2 inhibition revealed a programmed cell-death vulnerability engaged when the receptor is pharmacologically blocked.

    Evidence FGFR2 inhibitor with RIP1/MLKL/RIP3 knockdown, MST1 Co-IP, phospho-MLKL kinase assay, NF2 ubiquitination, YAP ChIP, and humanized xenografts

    PMID:40319089

    Open questions at the time
    • Why this pathway is RIP3-independent mechanistically unclear
    • Generality beyond squamous carcinoma untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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, PLCγ, and STAT3 outputs in a given cell.
  • No unified model linking isoform/compartment to specific downstream pathway choice
  • Quantitative rules governing ligand-dependent versus constitutive mutant signaling not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-5357801 Programmed Cell Death 1
Partners
ACAP1FRS2GRB2NEGR1PLCG1PTPN9SHP2

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. cDNA expression screening, ectopic overexpression, RNAi knockdown in cell lines Molecular cell High 19285943
2008 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. NIH 3T3 transformation assay, small-molecule kinase inhibition in mutant cell lines Proceedings of the National Academy of Sciences of the United States of America High 18552176
2008 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. FGFR2-selective small-molecule inhibitor, shRNA knockdown, phosphotyrosine immunoblotting in amplified cell lines Cancer research High 18381441
2005 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. Gene expression profiling, constitutive Sox2 expression, reporter assay, co-immunoprecipitation of Sox2–β-catenin The Journal of cell biology High 15781477
2013 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. In vitro kinase/phosphatase assays, FLIM-FRET, Co-IP, mutagenesis The Journal of cell biology High 23420874
2014 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. In vitro binding competition assay, NMR/biochemical mapping of binding site, phospholipase activity assay, calcium imaging, invasion assay Nature structural & molecular biology High 24440983
2006 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. Glycosylation inhibition, subcellular fractionation, ubiquitination assay, PLCγ phosphorylation assay, Frs2 co-immunoprecipitation in osteoblastic cells The Journal of biological chemistry Medium 16844695
1992 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. RNA blot analysis with multiple probes, cDNA isolation and sequencing Proceedings of the National Academy of Sciences of the United States of America Medium 1313574
2008 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. Migration/invasion assays with recombinant FGF10, isoform-specific receptor identification, RT-PCR for MT1-MMP and TGF-β1, ELISA for TGF-β1 protein British journal of cancer Medium 18594526
2018 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. Co-immunoprecipitation, in vivo cortical electroporation knockdown/rescue, Western blotting for p-ERK and p-AKT, FGFR2 surface degradation assay Brain : a journal of neurology High 30059965
2022 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. Transposon-based in vivo screen, tumor modelling in mice, in vitro functional compendium of FGFR2 variants, preclinical xenograft models, clinical trial correlation Nature High 35948633
2019 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. Co-culture of TAFs and cancer cells, FGFR2 inhibitor treatment, shRNA knockdown, phospho-immunoblotting for c-Src and HER2, mouse xenograft co-injection Clinical cancer research Medium 31699826
2021 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. Liver organoid transduction, mouse transplantation, MEK inhibitor combination experiments, in vitro and in vivo pharmacology Journal of hepatology High 33741397
2017 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. Conditional Fgfr2c knockout mice, genetic epistasis with Foxl2 knockout, immunofluorescence for SOX9/FOXL2 markers Endocrinology High 28938467
2017 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. p63-/- mouse genetic complementation with TAp63 or DeltaNp63 transgenes, Fgfr2-IIIb knockout mice, chromatin interaction analysis Proceedings of the National Academy of Sciences of the United States of America Medium 17626181
2023 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. Phosphatase activity assay, FGFR2-PTPN9 structural modeling, Co-IP, mutagenesis of interaction sites, in vitro and PDX pharmacology Hepatology (Baltimore, Md.) High 37505213
2011 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. Conditional knockout mice (Hoxb7-Cre), compound Fgfr2/Frs2α knockout, point mutation knock-in (Fgfr2LR/LR), 3D ureteric reconstruction Development (Cambridge, England) Medium 21350013
2020 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. Tamoxifen-inducible conditional knockout of Fgfr1, Fgfr2, Fgfr3 individually and combined in SPC+ cells, bleomycin injury model, flow cytometry, immunofluorescence American journal of respiratory cell and molecular biology High 31860803
2017 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. Fluorescent reporter knockin lines, genetic double knockout in mouse embryos and ESCs Developmental cell Medium 28552557
2021 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. Mouse mammary gland-specific FGFR2-S252W knock-in model, BRCA1 knockout epistasis, phospho-STAT3/ERK immunoblotting, YY1/PD-L1 expression analysis Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 34514747
2022 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. Ureteric epithelium-specific Fgfr2 conditional knockout, explant culture rescue with SHH/BMP4 agonists and antagonists, qPCR for Shh/Bmp4 Development (Cambridge, England) High 35020897
2022 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. mRNA sequencing, TCGA data analysis, TCF7 ChIP/luciferase reporter for SOX9, WNT3A stimulation, FGFR2/FGF7 siRNA, in vitro/in vivo validation Oncogene Medium 35428876
2023 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. CRISPR/Cas9 loss-of-function, pharmacological inhibition, ectodomain shedding assays, luciferase Notch reporter, xenograft models, transcriptomic analysis of patient cohort Clinical and translational medicine High 37165578
2021 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. shRNA knockdown, AKT/MAPK pathway inhibitors, EMT marker immunoblotting, flow cytometry for CSC markers in ESCC cell lines Cancer biology & therapy Medium 34224333
2018 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. CD151 siRNA knockdown, PKC inhibition, HuR knockdown, P-body visualization, Western blotting, diacylglycerol lipid profiling Journal of cell science Medium 30257985
2007 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. Bisulfite sequencing/methylation analysis, 5-aza-2'-deoxycytidine treatment, RT-PCR/Western blot for FGFR2 re-expression Biochemical and biophysical research communications Medium 17459342
2025 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. 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 Nature communications High 40319089
2019 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. CCA cell lines and patient-derived xenografts, MAPK/ERK phospho-immunoblotting, MEK inhibitor epistasis Journal of hepatology Medium 33741397
1992 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. Northern blot with isoform-specific probes, in situ hybridization, genomic analysis of exon proximity Cell growth & differentiation Medium 1419898

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Molecular cell 484 19285943
2023 Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. The New England journal of medicine 451 36652354
2008 Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proceedings of the National Academy of Sciences of the United States of America 302 18552176
2008 FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer research 244 18381441
2014 Activating FGFR2-RAS-BRAF mutations in ameloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 219 24993163
1995 Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Human molecular genetics 203 7795583
2005 Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation. The Journal of cell biology 189 15781477
2012 FGFR2 gene amplification and clinicopathological features in gastric cancer. British journal of cancer 161 22240789
2017 Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency. Developmental cell 144 28552557
1995 Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Human molecular genetics 142 8528214
2008 Cancer genomics and genetics of FGFR2 (Review). International journal of oncology 135 18636142
2007 DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proceedings of the National Academy of Sciences of the United States of America 134 17626181
2008 FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer. British journal of cancer 125 18594526
1996 Immunohistochemical detection of K-sam protein in stomach cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 118 9816310
2009 FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review). International journal of molecular medicine 114 19212647
2000 Expression of FGFR1, FGFR2 and FGFR3 during early neural development in the chick embryo. Mechanisms of development 108 10585567
2023 RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations. Cancer discovery 105 37270847
2022 Truncated FGFR2 is a clinically actionable oncogene in multiple cancers. Nature 97 35948633
2017 Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis. International journal of biological sciences 90 29230096
2017 SNORD126 promotes HCC and CRC cell growth by activating the PI3K-AKT pathway through FGFR2. Journal of molecular cell biology 86 27913571
2019 Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation. Clinical cancer research : an official journal of the American Association for Cancer Research 80 31699826
2013 Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma. International journal of oncology 77 23426935
2009 FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. The Journal of investigative dermatology 75 19387476
2024 Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 73 37843855
1992 K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase. Proceedings of the National Academy of Sciences of the United States of America 72 1313574
2013 Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. The Journal of cell biology 67 23420874
2018 NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice. Brain : a journal of neurology 65 30059965
2022 Genomic architecture of FGFR2 fusions in cholangiocarcinoma and its implication for molecular testing. British journal of cancer 62 35871236
2019 FGFR2 genomic aberrations: Achilles heel in the management of advanced cholangiocarcinoma. Cancer treatment reviews 57 31255945
2006 Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F. The Journal of biological chemistry 57 16844695
2021 FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma. Journal of hepatology 56 33741397
2019 Functions of FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma. Cytokine & growth factor reviews 56 31899106
1996 Isolation and characterization of ECT1 gene encoding CTP: phosphoethanolamine cytidylyltransferase of Saccharomyces cerevisiae. Journal of biochemistry 56 8982874
2014 Mutually exclusive FGFR2, HER2, and KRAS gene amplifications in gastric cancer revealed by multicolour FISH. Cancer letters 53 25086186
2011 FGFR2 alterations in endometrial carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 52 21725289
2022 FGFR2 Inhibition in Cholangiocarcinoma. Annual review of medicine 51 36170665
2009 Anti-acne agents attenuate FGFR2 signal transduction in acne. The Journal of investigative dermatology 50 19225542
2020 FGFR2 Is Required for AEC2 Homeostasis and Survival after Bleomycin-induced Lung Injury. American journal of respiratory cell and molecular biology 48 31860803
2009 FGFR2 as a molecular target in endometrial cancer. Future oncology (London, England) 48 19243295
2008 Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors. Breast cancer research and treatment 46 18563556
2017 FGFR2 is required for airway basal cell self-renewal and terminal differentiation. Development (Cambridge, England) 45 28348168
2016 miR-494 inhibits ovarian cancer cell proliferation and promotes apoptosis by targeting FGFR2. Oncology letters 42 27313773
2022 Wnt-TCF7-SOX9 axis promotes cholangiocarcinoma proliferation and pemigatinib resistance in a FGF7-FGFR2 autocrine pathway. Oncogene 40 35428876
2014 Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion. Nature structural & molecular biology 39 24440983
2015 Tissue-specific roles of Fgfr2 in development of the external genitalia. Development (Cambridge, England) 38 26081573
2008 Roles of FGFR2 and twist in human craniosynostosis: insights from genetic mutations in cranial osteoblasts. Frontiers of oral biology 37 18391499
2017 Testis Determination Requires a Specific FGFR2 Isoform to Repress FOXL2. Endocrinology 36 28938467
2000 Clustering of FGFR2 gene mutations inpatients with Pfeiffer and Crouzon syndromes (FGFR2-associated craniosynostoses). Cytogenetics and cell genetics 35 11173845
2021 Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 34 34514747
2002 Expression of the FGF receptor 2 gene (fgfr2) during embryogenesis in the zebrafish Danio rerio. Mechanisms of development 33 14516681
2022 CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction. Molecular medicine (Cambridge, Mass.) 32 36463112
2018 FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis and lung cancer. Oncology letters 32 30013642
2024 Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies. Clinical cancer research : an official journal of the American Association for Cancer Research 31 39226398
2008 FGFR2 signaling and the pathogenesis of acne. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 29 19000061
2018 FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro. Molecular oncology 28 29573334
2021 Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas. Cell death & disease 27 33692336
2014 Methylation of the FGFR2 gene is associated with high birth weight centile in humans. Epigenomics 27 25431941
2022 Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments. OncoTargets and therapy 26 36238135
2011 Independent roles of Fgfr2 and Frs2alpha in ureteric epithelium. Development (Cambridge, England) 26 21350013
2019 Intrinsic FGFR2 and Ectopic FGFR1 Signaling in the Prostate and Prostate Cancer. Frontiers in genetics 25 30761180
2019 Genetic Polymorphisms in FGFR2 Underlie Skeletal Malocclusion. Journal of dental research 25 31509720
2010 The missense mutation W290R in Fgfr2 causes developmental defects from aberrant IIIb and IIIc signaling. Developmental dynamics : an official publication of the American Association of Anatomists 25 20503384
2018 MicroRNA-1266 suppresses papillary thyroid carcinoma cell metastasis and growth via targeting FGFR2. European review for medical and pharmacological sciences 24 29917195
2022 FGFR2 accommodates osteogenic cell fate determination in human mesenchymal stem cells. Gene 23 35093449
2020 Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment. Cells 23 32751911
2019 MicroRNA-889-3p targets FGFR2 to inhibit cervical cancer cell viability and invasion. Experimental and therapeutic medicine 23 31316631
2023 ECT9 condensates with ECT1 and regulates plant immunity. Frontiers in plant science 22 37113599
2017 FGFR2 amplification in colorectal adenocarcinoma. Cold Spring Harbor molecular case studies 22 28835367
2023 Circular RNA circSMAD4 regulates cardiac fibrosis by targeting miR-671-5p and FGFR2 in cardiac fibroblasts. Molecular therapy. Nucleic acids 19 38046397
2022 FGF7/FGFR2-JunB signalling counteracts the effect of progesterone in luminal breast cancer. Molecular oncology 19 35726195
2022 Incidence of FGFR2 Amplification and FGFR2 Fusion in Patients with Metastatic Cancer Using Clinical Sequencing. Journal of oncology 18 35342406
2016 TNRC9 rs12443621 and FGFR2 rs2981582 polymorphisms and breast cancer risk. World journal of surgical oncology 18 26911390
2023 FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways. Clinical and translational medicine 17 37165578
2019 Hydrocephalus and Chiari malformation pathophysiology in FGFR2-related faciocraniosynostosis: A review. Neuro-Chirurgie 17 31525395
2022 FGFR mRNA Expression in Cholangiocarcinoma and Its Correlation with FGFR2 Fusion Status and Immune Signatures. Clinical cancer research : an official journal of the American Association for Cancer Research 16 36190545
2009 A single-point mutation in FGFR2 affects cell cycle and Tgfbeta signalling in osteoblasts. Biochimica et biophysica acta 16 20004243
2023 Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach. ACS medicinal chemistry letters 15 36923909
2021 FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas. Molecular oncology 15 34850536
2024 The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations. Clinical cancer research : an official journal of the American Association for Cancer Research 14 38437671
2023 PTPN9 dephosphorylates FGFR2 pY656/657 through interaction with ACAP1 and ameliorates pemigatinib effect in cholangiocarcinoma. Hepatology (Baltimore, Md.) 14 37505213
2022 Identification and characterization of FGFR2+ hematopoietic stem cell-derived fibrocytes as precursors of cancer-associated fibroblasts induced by esophageal squamous cell carcinoma. Journal of experimental & clinical cancer research : CR 14 35941662
2023 Downregulated ESRP1/2 promotes lung metastasis of bladder carcinoma through altering FGFR2 splicing and macrophage polarization. Frontiers in immunology 13 37090731
2021 Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma. NPJ precision oncology 13 34480077
2019 miR-628 reduces prostate cancer proliferation and invasion via the FGFR2 signaling pathway. Experimental and therapeutic medicine 13 31316598
1992 Tissue-specific expression of two isoforms of chicken fibroblast growth factor receptor, bek and Cek3. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 13 1419898
2023 Inhibitory effect and mechanism of Lactobacillus crispatus on cervical precancerous cells Ect1/E6E7 and screening of early warning factors. Infectious agents and cancer 12 36726132
2021 FGFR2-IIIb Expression by Immunohistochemistry Has High Specificity in Cholangiocarcinoma with FGFR2 Genomic Alterations. Digestive diseases and sciences 12 34773565
2019 The growth of the posterior cranial fossa in FGFR2-induced faciocraniosynostosis: A review. Neuro-Chirurgie 12 31557489
2018 CD151 regulates expression of FGFR2 in breast cancer cells via PKC-dependent pathways. Journal of cell science 12 30257985
2017 Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia. Oncotarget 12 29152066
2015 FGFR1 and FGFR2 in fibrolamellar carcinoma. Histopathology 12 26259677
2023 Spatial distribution and functional relevance of FGFR1 and FGFR2 expression for glioblastoma tumor invasion. Cancer letters 11 37579831
2022 FGFR2 signaling enhances the SHH-BMP4 signaling axis in early ureter development. Development (Cambridge, England) 11 35020897
2022 Validation and Characterization of FGFR2 Rearrangements in Cholangiocarcinoma with Comprehensive Genomic Profiling. The Journal of molecular diagnostics : JMD 11 35176488
2022 Pemigatinib in cholangiocarcinoma with a FGFR2 rearrangement or fusion. Expert review of anticancer therapy 11 36408971
2021 FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma. Cancer biology & therapy 11 34224333
2016 FGFR2 mutation in a Chinese family with unusual Crouzon syndrome. International journal of ophthalmology 11 27803855
2007 Aberrant hypermethylation of the FGFR2 gene in human gastric cancer cell lines. Biochemical and biophysical research communications 11 17459342
1999 A novel FGFR2 gene mutation in Crouzon syndrome associated with apparent nonpenetrance. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 11 10574673
2025 Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy. Nature communications 10 40319089

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