Affinage

FRS2

Fibroblast growth factor receptor substrate 2 · UniProt Q8WU20

Length
508 aa
Mass
57.0 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FRS2 (fibroblast growth factor receptor substrate 2) is a lipid-anchored scaffold protein that couples multiple receptor tyrosine kinases—principally FGFRs, but also TrkA/B, RET, ALK, and VEGFR—to the Ras/MAPK and PI3K/Akt signaling cascades, and is essential for embryonic viability, organogenesis, and postnatal vascular development. FRS2α constitutively associates with the FGFR juxtamembrane region via its PTB domain (or binds TrkA/RET at NPXpY motifs upon phosphorylation), and upon receptor activation is tyrosine-phosphorylated to recruit Grb2 (linking to Sos/Ras/MAPK, Gab1/PI3K, and Cbl-mediated receptor ubiquitination) and Shp2 (sustaining ERK activation), with the Shp2-binding sites being critically required for lens and retinal induction (PMID:10629055, PMID:9632781, PMID:15569927, PMID:11997436). Plasma membrane targeting requires coupled N-myristoylation and palmitoylation at Gly2/Cys4/Cys5, and pharmacological or genetic disruption of this lipid modification blocks FGFR-dependent PI3K/Akt and MAPK signaling and suppresses tumor growth (PMID:31184863, PMID:29540482). Activated ERK constitutively associates with FRS2α and phosphorylates it on threonine residues, attenuating tyrosine phosphorylation and creating a negative feedback loop that limits signaling output (PMID:12419216, PMID:12974390).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Establishing that FRS2 is the principal docking protein linking FGF-activated receptors to sustained MAPK signaling resolved how FGF receptor kinase activity is transmitted to cytoplasmic effectors: FRS2 recruits both Grb2–Sos and Shp2, and Shp2 catalytic activity is specifically required for sustained ERK activation and PC12 differentiation.

    Evidence Co-immunoprecipitation, FRS2 point mutants deficient in Grb2/Shp2 binding, PC12 differentiation assays, Shp2 catalytic mutants

    PMID:9632781

    Open questions at the time
    • Relative contributions of Grb2 vs. Shp2 arms not quantitatively parsed
    • Mechanism by which Shp2 sustains ERK activation not defined
  2. 2000 High

    Demonstrating that the FRS2 PTB domain binds FGFR1 constitutively (phosphorylation-independent) but TrkA only at phospho-Y490 (NPXpY) established that FRS2 uses fundamentally different receptor-engagement modes for different RTKs, explaining how one adaptor can serve multiple receptor systems.

    Evidence Deletion/alanine scanning mutagenesis, peptide competition, direct binding assays

    PMID:10629055

    Open questions at the time
    • Structural basis for phosphorylation-independent FGFR binding not yet resolved at atomic level
    • In vivo stoichiometry of FRS2–receptor complexes unknown
  3. 2001 High

    Genetic knockout of FRS2α caused embryonic lethality at E7.0–7.5 and impaired MAPK, PI3K, chemotaxis, and proliferation in fibroblasts, definitively establishing FRS2α as an essential, non-redundant signaling node downstream of FGFRs in vivo.

    Evidence FRS2α-null mice (homologous recombination), FRS2α-deficient fibroblast signaling assays

    PMID:11447289

    Open questions at the time
    • Contribution of FRS2β to residual signaling not assessed
    • Gastrulation-specific effectors downstream of FRS2α not identified
  4. 2001 High

    Showing that FRS2 binds RET at phospho-Y1062 and contributes to RET-dependent MAPK signaling—with HSCR-associated RET mutants impaired in FRS2 binding—extended FRS2 function beyond FGFR/Trk to a third RTK family and linked it to a developmental disease context.

    Evidence Co-IP, Y1062 mutagenesis, MAPK/proliferation assays; differential complex composition (FRS2-RET recruits Grb2 but not Gab1)

    PMID:11360177 PMID:11390647

    Open questions at the time
    • Whether FRS2-RET vs. Shc-RET competition is regulated in vivo is unknown
    • Direct role of FRS2 in Hirschsprung disease pathogenesis not genetically proven
  5. 2002 High

    Discovery that ERK/MAPK phosphorylates FRS2α on threonine residues to attenuate its tyrosine phosphorylation identified a direct negative feedback loop, explaining how FRS2 signaling is self-limiting and how non-FGF stimuli (insulin, EGF, PDGF) can cross-inhibit FRS2-dependent signaling.

    Evidence Threonine-to-alanine mutants, in vivo phosphorylation assays, soft-agar colony formation, migration and proliferation assays

    PMID:12419216 PMID:12974390

    Open questions at the time
    • Specific threonine residues mediating feedback not all mapped
    • Whether feedback operates identically downstream of all FRS2-coupled RTKs is untested
  6. 2002 High

    Identification of the FRS2α–Grb2–Cbl ternary complex revealed that FRS2α simultaneously organizes signal amplification (Sos, PI3K) and signal termination (Cbl-mediated ubiquitination of FGFR and FRS2α itself), unifying positive and negative regulation on one scaffold.

    Evidence Co-IP, ubiquitination assays, FRS2α-null fibroblast rescue

    PMID:11997436

    Open questions at the time
    • Kinetics and relative rates of Sos vs. Cbl recruitment not determined
    • Whether Cbl ubiquitinates FRS2α directly or via the receptor is unresolved
  7. 2002 High

    Biophysical analysis (ITC, NMR) revealed that FRS2α PTB domain uses an enthalpy-driven mode for phospho-TrkA/B binding and an entropy-driven mode for unphosphorylated FGFR, with structurally distinct binding pockets, providing the first mechanistic explanation for dual receptor recognition.

    Evidence Isothermal titration calorimetry, NMR spectral analysis, site-directed mutagenesis; later confirmed by NMR structure of PTB–phospho-TrkB complex

    PMID:11877385 PMID:24470253

    Open questions at the time
    • Full-length FRS2α structure not determined
    • How C-terminal tail auto-inhibits PTB binding in the absence of receptor activation not structurally resolved
  8. 2004 High

    Genetic dissection of FRS2α phosphorylation sites in knock-in mice showed that the two Shp2-binding tyrosines are essential for lens and retinal induction (via sustained ERK), while the four Grb2-binding tyrosines are dispensable, resolving which downstream arm drives eye organogenesis.

    Evidence Frs2α2F/2F and Frs2α4F/4F knock-in mice, embryological phenotyping, ERK activation, marker gene expression

    PMID:15569927

    Open questions at the time
    • Whether Shp2 vs. Grb2 site-specific requirements generalize to other tissues not fully explored
    • Downstream transcriptional targets of FRS2α-Shp2 arm incompletely defined
  9. 2011 Medium

    Demonstrating that FRS2α-dependent FGF signaling suppresses autophagy via PI3K/Akt/mTOR in cardiac progenitors and MEFs placed FRS2α upstream of mTOR-regulated autophagy, adding a cell-fate (differentiation timing) dimension to FRS2 function beyond classical MAPK/proliferation.

    Evidence Tissue-specific conditional KO of FRS2α/FGFRs in cardiac progenitors, FRS2α-null MEFs, pathway inhibitors, autophagy and differentiation assays

    PMID:21927580 PMID:22207710

    Open questions at the time
    • Whether FRS2α-autophagy axis operates in non-cardiac tissues not tested
    • Direct vs. indirect regulation of mTOR by FRS2α not dissected
  10. 2014 High

    Endothelial-specific deletion of FRS2α revealed its essential role in VEGFR-dependent ERK activation and postnatal angiogenesis, lymphangiogenesis, and arteriogenesis, extending FRS2α function to a fourth RTK family (VEGFRs) and vascular biology.

    Evidence Frs2α iECKO conditional KO, ERK activation, endothelial migration/proliferation, in vivo vascular phenotyping

    PMID:24706887

    Open questions at the time
    • Which VEGFR isoform directly phosphorylates FRS2α not determined
    • Whether FRS2α binds VEGFR directly or via an intermediary is unresolved
  11. 2019 High

    Characterizing coupled myristoylation–palmitoylation (at G2, C4, C5) as the dual-lipid targeting mechanism for FRS2α plasma membrane localization, and demonstrating that pharmacological NMT inhibition blocks FGFR oncogenic signaling and tumor growth, established membrane anchoring as a druggable vulnerability.

    Evidence Palmitoylation assay, C4A/C5A/G2A mutagenesis, fluorescence fluctuation spectroscopy, NMT inhibitor B13 in vitro and xenograft models

    PMID:29540482 PMID:31184863

    Open questions at the time
    • Identity of the palmitoyl acyltransferase(s) responsible for FRS2α palmitoylation unknown
    • Whether lipid raft localization is functionally required vs. correlative remains unresolved
  12. 2025 High

    Epistatic analysis of Frs2, Shp2, Shc1, and Grb2 deletion in mouse lens showed that Shc1 cooperates with FRS2/Shp2 to recruit Grb2 for MAPK activation during fiber cell differentiation, and that Grb2 is the essential convergence node, refining the combinatorial logic of adaptor usage in FGF signaling in vivo.

    Evidence Quadruple tissue-specific conditional KO in mouse lens, MAPK assays, lens phenotyping

    PMID:40327534

    Open questions at the time
    • Whether Shc1 compensation for FRS2 loss occurs in non-lens tissues is unknown
    • Quantitative contribution of each adaptor to Grb2 recruitment not measured biochemically

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length structure of FRS2α and how the C-terminal tail auto-inhibits PTB domain binding; the identity of the palmitoyl acyltransferase(s) that palmitoylate FRS2α; the mechanism by which FRS2α interfaces with VEGFRs (direct binding vs. intermediary); and whether targeting the FRS2α PTB domain pharmacologically achieves sufficient selectivity for clinical translation.
  • No full-length structure of FRS2α exists
  • Palmitoyl acyltransferase identity unknown
  • VEGFR–FRS2α binding mechanism not biochemically defined
  • PTB domain inhibitor selectivity and in vivo pharmacology not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 5 R-HSA-9612973 Autophagy 2
Partners
CBLFGFR1GAB1GRB2RETSHC1SHP2TRKA

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 The PTB domains of FRS2α and FRS2β bind directly to the juxtamembrane region of FGFR1 constitutively (phosphorylation-independent), whereas binding to TrkA (NGF receptor) requires phosphorylation of Y490 (an NPXpY motif). The C-terminal tail of FRS2 contains multiple SH2-domain binding sites for Grb2 and Shp2. Deletion and alanine scanning mutagenesis, peptide competition assays, direct binding assays Molecular and cellular biology High 10629055
1998 FRS2 forms a complex with the N-terminal SH2 domain of Shp2 upon FGF stimulation; this complex also contains Grb2 and Sos1. An FRS2 mutant deficient in both Grb2 and Shp2 binding fails to sustain MAP kinase activation and cannot induce PC12 cell differentiation. Shp2 catalytic activity is required for sustained ERK activation downstream of FRS2. Co-immunoprecipitation, FRS2 point mutants, PC12 differentiation assays, Shp2 catalytic mutants Molecular and cellular biology High 9632781
2001 Targeted disruption of FRS2α in mice causes embryonic lethality at E7.0–E7.5. In FRS2α-deficient fibroblasts, FGF-induced MAP kinase stimulation, PI-3 kinase activation, chemotactic response, and cell proliferation are severely impaired. Tyrosine-phosphorylated FRS2α serves as a scaffold for assembly of a multiprotein complex including Gab1 and downstream effector proteins. Distinct tyrosine phosphorylation sites on FRS2α mediate different FGF-induced biological responses. Gene knockout (homologous recombination), FRS2α-deficient fibroblast assays (MAPK, PI3K, chemotaxis, proliferation) Proceedings of the National Academy of Sciences of the United States of America High 11447289
2002 FRS2α is phosphorylated by MAP kinase on multiple threonine residues in response to FGF stimulation (and by insulin, EGF, PDGF without inducing FRS2α tyrosine phosphorylation). Prevention of FRS2α threonine phosphorylation results in constitutive tyrosine phosphorylation of FRS2α in unstimulated cells and enhanced signaling (MAPK activation, migration, proliferation), revealing a MAPK-mediated negative feedback mechanism. In vivo phosphorylation assays, FRS2α threonine-to-alanine mutants, soft agar colony formation, cell migration and proliferation assays Molecular cell High 12419216
2002 Grb2 bound to tyrosine-phosphorylated FRS2α forms a ternary complex with the E3 ubiquitin ligase Cbl via Grb2 SH3 domains, resulting in ubiquitination of the FGF receptor and FRS2α in response to FGF stimulation. This demonstrates FRS2α assembles both positive (Sos, PI3K) and negative (Cbl) signaling proteins to regulate FGF signal attenuation. Co-immunoprecipitation, ubiquitination assays, FRS2α-/- fibroblast rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 11997436
2001 The docking protein FRS2 is tyrosine-phosphorylated by ligand-stimulated and constitutively active oncogenic forms of RET receptor tyrosine kinase. FRS2 PTB domain binds to phospho-Y1062 in RET (the same site as Shc). FRS2-RET interaction activates MAP kinase signaling; HSCR-associated RET mutants with impaired FRS2 binding show reduced MAP kinase activation. Co-immunoprecipitation, site-directed mutagenesis (pY1062), MAP kinase activation assays, cell proliferation assays Molecular and cellular biology High 11390647
1999 The PTB domain of FRS2 binds the Trk receptors at the same phosphotyrosine residue (NPXpY) that binds Shc, suggesting competitive binding between FRS2 and Shc to TrkA regulates differentiation versus proliferation. FRS2 also binds Grb2, Crk, SH-PTP-2, p13(suc1), and the SH3 domain of Src. Direct binding assays, yeast two-hybrid, overexpression of FRS2 in TrkA mutant cells with functional differentiation readout The Journal of biological chemistry High 10092678
2001 The FRS2/3-binding site on FGFR1 (in the juxtamembrane region) is required for some but not all Fgfr1 developmental functions. Fgfr1ΔFrs/ΔFrs mice die during late embryogenesis with defects in neural tube closure, tail bud and pharyngeal arch development, but the mutant receptor still drives normal MAPK responses and Fgfr1 functions during gastrulation/somitogenesis, indicating context-specific Frs-dependent and Frs-independent signaling. Knock-in mice with deletion of Frs2/3-binding site on Fgfr1, embryological analysis, MAPK activation assays Development (Cambridge, England) High 16421190
1997 FRS2α is myristoylated at its N-terminus; this lipid modification is important for its localization to the plasma membrane and its ability to stimulate downstream signaling. (Referenced in PMID:29540482 and PMID:31184863 as the original myristoylation study by Kouhara et al.) N-myristoylation identification, membrane localization assays Referenced in corpus but original PMID not in corpus Medium 18452557 29540482
2019 FRS2α undergoes palmitoylation at cysteines 4 and 5 in addition to N-myristoylation; mutation of these cysteines reduces FRS2α localization to the plasma membrane (quantified by fluorescence fluctuation spectroscopy). G2A mutation (preventing myristoylation) also abrogates palmitoylation, indicating coupled myristoylation-palmitoylation governs membrane targeting. Palmitoylation biochemical assay, site-directed mutagenesis (C4A/C5A, G2A), fluorescence fluctuation spectroscopy for PM localization quantification Biochemistry High 31184863
2018 Loss of myristoylation of FRS2α (pharmacologically via the NMT inhibitor B13) inhibits FGF/FGFR-mediated oncogenic signaling, reduces PI3K/AKT and MAPK signaling, and inhibits tumor growth in xenograft models. Myristoylated FRS2α is required for membrane localization and efficient FGFR signal transmission. Pharmacological inhibition of N-myristoyltransferase (B13), FRS2α phosphorylation assays, PI3K/MAPK assays, xenograft tumor models The Journal of biological chemistry High 29540482
2004 Tyrosine phosphorylation sites on FRS2α responsible for Shp2 recruitment (two sites, Frs2α2F mutant) are critical for eye development (lens and retina induction), as Frs2α2F/2F mice show anophthalmia/microphthalmia with reduced ERK activation and decreased Pax6, Six3, Chx10, and Bmp4 expression. Grb2-binding sites (Frs2α4F mutant) are dispensable for early eye development. Knock-in mice with point mutations in Shp2- or Grb2-binding sites of FRS2α, embryological phenotyping, ERK activation assays, marker gene expression Proceedings of the National Academy of Sciences of the United States of America High 15569927
2001 The VT motif (valine-threonine) in the alternatively spliced juxtamembrane region of FGFR1 is required for FRS2 interaction with Fgfr1. The VT+ receptor isoform supports Erk2 phosphorylation, while VT- does not bind FRS2, indicating that alternative splicing of the juxtamembrane domain regulates FGFR1-FRS2 interaction and downstream MAPK signaling. Co-immunoprecipitation of FRS2 with Fgfr1 juxtamembrane domain variants, Erk2 phosphorylation assays The Journal of biological chemistry High 11729184
2002 The FRS2α PTB domain adopts different binding modes for phosphorylated TrkA/TrkB (enthalpy-driven, recognizing NPXpY) versus unphosphorylated FGFR juxtamembrane region (entropy-driven). NMR analysis shows that disruption of an unstructured C-terminal region adjacent to the PTB domain alters residues at the ligand-binding site, and structural disruption of the β8-strand weakens FGFR ligand association. Isothermal titration calorimetry, NMR spectral analysis, site-directed mutagenesis The Journal of biological chemistry High 11877385
2014 NMR structure of the FRS2α PTB domain bound to phosphorylated TrkB reveals two distinct but adjacent pockets: one for constitutive interaction with unphosphorylated FGFR juxtamembrane region, and one for phosphotyrosine-dependent binding to TrkA/TrkB, showing mutually exclusive binding mechanisms. NMR structure determination with phosphorylated TrkB peptide Proteins High 24470253
2001 FRS2 PTB domain binds to RET at phospho-Y1062, the same residue bound by Shc. While Shc-RET complex recruits GRB2 and GAB1, FRS2-RET complex recruits GRB2 only (not GAB1), linking RET preferentially to the RAS/MAPK pathway but not the PI3K/AKT pathway. Phosphorylated FRS2 also directly complexes with Shp2. Co-immunoprecipitation, site-directed mutagenesis (Y1062), kinase activity assays Oncogene High 11360177
2003 FRS2 is localized exclusively to lipid raft membrane microdomains in neuroblastoma cells in vitro and in vivo. FGF2-induced signaling through FRS2 occurs within lipid rafts. Activation of PKC, Src family kinases, and MEK1/2 regulates serine-threonine phosphorylation of FRS2 within lipid rafts, which in turn modulates FRS2 phosphotyrosine levels. Grb2 is recruited to lipid rafts during FGF2 signaling. Lipid raft fractionation, phosphorylation assays, pharmacological inhibitors, co-immunoprecipitation The Journal of biological chemistry Medium 12571252
2002 The adaptor protein Shb binds to phospho-Y766 of FGFR-1 via its SH2 domain and regulates FRS2 phosphorylation and Ras/MEK/MAPK signaling. Overexpression of an SH2-domain mutant Shb dramatically reduces FGFR-1-mediated FRS2 phosphorylation and impairs FGF-mediated mitogenicity. Chimeric receptor system, co-immunoprecipitation, dominant-negative Shb SH2 mutant, FRS2 phosphorylation assays, mitogenicity assays Molecular biology of the cell Medium 12181353
2004 FRS2-dependent activation of SRC family kinases (including SRC itself) is required for FGF receptor-induced phosphorylation of Sprouty2 at Y55. SRC forms a complex with hSpry2, and phosphorylation of hSpry2 is required for it to inhibit ERK pathway activation. Thus, FRS2 bridges FGFR kinase activity to SRC-mediated activation of a negative regulatory (Sprouty) pathway. SRC family kinase-specific inhibitor, SRC-deficient mutant cells, co-immunoprecipitation of SRC-hSpry2 complex, phosphorylation assays Journal of cell science Medium 15564375
2003 ERK1/2 constitutively associates with the central portion of FRS2 and phosphorylates the FRS2 C-terminal region on serine/threonine residues in response to EGF and FGF stimulation. Inhibition of ERK1/2 by U0126 enhances FRS2 tyrosine phosphorylation, establishing a negative feedback loop whereby activated ERK1/2 phosphorylates FRS2 on serine/threonine to downregulate its tyrosine phosphorylation. MEK inhibitor (U0126), in vitro kinase assay, co-immunoprecipitation of ERK-FRS2, phosphorylation assays Biological chemistry Medium 12974390
1999 FRS2 associates with atypical PKC isoforms (PKCλ and PKCζ) in FGF-stimulated Swiss 3T3 cells. The interaction is likely direct (yeast two-hybrid) and is mediated by the C-terminal region of FRS2 (residues 300–508) binding to the catalytic domain of PKCλ (residues 240–562). Constitutively active PKCλ binds FRS2 with higher affinity. FRS2 is not a substrate for PKCλ or PKCζ, suggesting FRS2 functions as an anchoring protein for activated atypical PKCs. Co-immunoprecipitation, yeast two-hybrid, in vitro kinase assay The Journal of biological chemistry Medium 10383403
2005 Rnd1 (a Rho family GTPase) directly associates with FRS2α and FRS2β. The interaction of FRS2β with Rnd1 suppresses Rnd1's inhibitory effect on RhoA. Upon FGFR1 activation, FRS2β is phosphorylated, recruits Shp2, and releases Rnd1; the liberated Rnd1 then inhibits RhoA activity. Knockdown of Rnd1 suppresses FGF-induced neurite outgrowth in PC12 cells. Direct binding assays, co-immunoprecipitation, RhoA activity assays, siRNA knockdown, neurite outgrowth assay The Journal of biological chemistry Medium 15738000
2001 Xenopus FRS2 (xFRS2) is tyrosine-phosphorylated in early embryos. An unphosphorylatable xFRS2 mutant interferes with FGF-dependent mesoderm formation. The Src family kinase Laloo binds to xFRS2 and XFGFR1 and promotes tyrosine phosphorylation of xFRS2, indicating FRS2 functions in FGF signaling in cooperation with Laloo during vertebrate development. Overexpression of dominant-negative FRS2 in Xenopus embryos, co-immunoprecipitation of xFRS2-Laloo-FGFR1 complex, phosphorylation assays, mesoderm formation assays EMBO reports Medium 11463744
2007 FGFR1 tyrosine autophosphorylation (but not at the FRS2α-binding juxtamembrane site itself) is required for optimal full-length FRS2α binding to FGFR1. The C-terminal sequence downstream of the FRS2α PTB domain inhibits constitutive PTB-FGFR1 binding (truncated PTB alone binds constitutively). FRS2β does not show activation-enhanced binding. The Grb2-binding sites of FRS2α are essential for mediating FGFR1 signals to activate the FiRE enhancer of the syndecan 1 gene. Co-immunoprecipitation of full-length vs. truncated FRS2α with kinase-dead and phospho-site mutant FGFR1, FiRE enhancer-luciferase reporter assay Molecular endocrinology (Baltimore, Md.) Medium 17901128
2010 EphA4 directly interacts with the FRS2α PTB domain upon tyrosine phosphorylation of the EphA4 juxtamembrane domain, and EphA4 directly phosphorylates FRS2α. FRS2α PTB domain and EphA4 simultaneously bind distinct regions of the FGFR juxtamembrane domain, forming a ternary EphA4/FGFR/FRS2α complex. Dominant-negative EphA4 or truncated FRS2α inhibits ligand-dependent proliferation of embryonic neural stem/progenitor cells. Yeast two-hybrid, in vitro binding and kinase assays, dominant-negative experiments, neural stem/progenitor cell proliferation assays Genes to cells : devoted to molecular & cellular mechanisms Medium 20184660
2014 FRS2α plays a critical role in VEGF receptor signaling: it regulates VEGF-A and VEGF-C-dependent ERK activation and endothelial cell migration/proliferation in vitro. Endothelial-specific deletion of FRS2α in vivo causes profound impairment of postnatal vascular development, angiogenesis, lymphangiogenesis, and arteriogenesis. Endothelial-specific conditional KO of FRS2α (Frs2α iECKO), ERK activation assays, endothelial cell migration/proliferation assays, in vivo vascular phenotyping Proceedings of the National Academy of Sciences of the United States of America High 24706887
2011 FRS2α-mediated FGF signals suppress autophagy via PI3K/Akt/mTOR pathway. Disruption of FGF signaling (via tissue-specific ablation of FGFRs or FRS2α in cardiac progenitor cells) increases autophagy and leads to premature differentiation of cardiac progenitor cells. Activating autophagy promotes myocardial differentiation, while inhibiting it prevents premature differentiation. Tissue-specific conditional KO of FRS2α and FGFRs in heart progenitors, embryoid body cultures, autophagy assays, differentiation assays Circulation research Medium 22207710
2011 FRS2α is essential for FGF signaling to activate mTOR via the PI3K/Akt pathway and to suppress autophagy in mouse embryonic fibroblasts. FRS2α-null MEFs show impaired mTOR activation and increased autophagy in response to FGF. Frs2α-null MEFs, pathway inhibitors (PI3K, mTOR), mTOR/autophagy assays International journal of biological sciences Medium 21927580
2008 The FGFR2 IIIb C3 splice isoform (lacking Y770 in the YXXL motif) exhibits persistent FRS2 binding to FGFR2, enhanced FRS2 tyrosine phosphorylation, and increased transforming activity. Loss of Y770 enhances FRS2 binding to FGFR2 IIIb, and FRS2 binding to FGFR2 is required for the increased tyrosine phosphorylation and enhanced transformation caused by the Y770F mutation. Site-directed mutagenesis (Y770, L773), co-immunoprecipitation, FRS2 phosphorylation assays, transformation/soft agar assays The Journal of biological chemistry Medium 19103595
2000 FRS2 is phosphorylated by the insulin receptor in vitro (in vitro kinase assay with purified IR and GST-FRS2) and in intact cells upon insulin stimulation. Insulin-induced FRS2 tyrosine phosphorylation leads to association with Shp2, suggesting FRS2 may function as a docking molecule in insulin signaling analogous to IRS proteins. Yeast two-hybrid screen, in vitro kinase assay, co-immunoprecipitation in PC12/IR cells Endocrinology Medium 10650943
2008 RET-mediated cell migration requires FRS2 adaptor function at Y1062 of RET. FRS2 selectively recruits RET to focal complexes (membrane foci), leading to activation of SRC family kinases and FAK. SRC activation also depends on direct RET interaction at Y981. The two sites in concert regulate directional cell migration. Co-immunoprecipitation, localization to focal complexes (microscopy), SRC/FAK activation assays, cell migration assays, neuroepitheliomal cell functional assays Journal of cellular biochemistry Medium 18189271
2007 FRS2 is recruited to and phosphorylated by ALK (anaplastic lymphoma kinase) following antibody-based ALK activation in PC12 cells, likely at a non-canonical (non-NPXpY) phosphotyrosine site. FRS2 contributes to ALK-dependent MAP kinase activation and neuronal differentiation. Co-immunoprecipitation, tyrosine phosphorylation assays, site-directed mutagenesis of ALK binding sites, PC12 differentiation assays FEBS letters Medium 17274988
2014 FRS2α mediates hepatic FGF15/19-FGFR4 signaling to regulate bile acid homeostasis by controlling Cyp7a1 (cholesterol 7α-hydroxylase) expression. Ablation of Frs2α in hepatocytes abrogates the repression of Cyp7a1 induced by FGF15/FGF19-FGFR4 signaling, demonstrating FRS2α is required downstream of FGFR4 for bile acid production control. Hepatocyte-specific conditional KO of Frs2α, Cyp7a1 expression assays, FGF15/19 treatment experiments Current molecular medicine Medium 25056539
2025 FRS2 and Shp2 cooperate with Shc1 to recruit Grb2 for FGF-induced MAPK signaling during lens development. Deletion of Frs2 and Shp2 together primarily impacts late lens vesicle development (fiber cell differentiation), and loss of Shc1 exacerbates this defect. Grb2 deletion abolishes MAPK signaling with profound arrest of lens development. FGF signaling is required for phosphorylation of Grb2-binding sites on Shc1, establishing Shc1 as a critical collaborator with Frs2/Shp2 for Grb2 recruitment. Genetic ablation of Frs2, Shp2, Shc1, Grb2 in mouse lens (conditional KO), MAPK activation assays, lens development phenotyping eLife High 40327534
2019 A small molecule targeting the PTB domain of FRS2 prevents FRS2 activation and interrupts FGFR signaling, stalling FGFR-dependent matrix invasion in cancer models in vitro and reducing tumor growth in vivo in an ovarian cancer xenograft model. Pharmacophore-based screening, biophysical binding assays, cell invasion assays, xenograft tumor model, thermal proteome profiling Cellular oncology (Dordrecht, Netherlands) Medium 36495366
2019 FRS2α undergoes palmitoylation dependent on prior myristoylation (G2A mutation abrogates palmitoylation), establishing a coupled myristoylation-palmitoylation modification mechanism that regulates plasma membrane localization. Palmitoylation assay, G2A and C4A/C5A mutagenesis, fluorescence fluctuation spectroscopy (quantitative PM localization) Biochemistry High 31184863

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Molecular and cellular biology 286 10629055
1998 Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Molecular and cellular biology 282 9632781
2001 Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways. Proceedings of the National Academy of Sciences of the United States of America 250 11447289
2008 Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer science 202 18452557
1999 The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. The Journal of biological chemistry 189 10092678
2002 FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proceedings of the National Academy of Sciences of the United States of America 155 11997436
2002 The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Molecular cell 130 12419216
2001 Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Molecular and cellular biology 113 11390647
2006 Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development. Development (Cambridge, England) 106 16421190
2013 Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma. Cancer research 87 23393200
2001 Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. Oncogene 87 11360177
2002 The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells. Molecular biology of the cell 76 12181353
2011 FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity. Circulation research 75 22207710
2004 Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina. Proceedings of the National Academy of Sciences of the United States of America 75 15569927
2005 The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development. Molecular and cellular biology 73 15870281
2019 Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer. Nature communications 68 30755618
2014 FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation. PLoS genetics 63 24465223
2004 FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts. FEBS letters 61 15094036
2008 Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform. The Journal of biological chemistry 59 19103595
2005 Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells. Proceedings of the National Academy of Sciences of the United States of America 59 16239343
2008 Frs2alpha-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis. Development (Cambridge, England) 58 18832393
2001 Association of the signaling adaptor FRS2 with fibroblast growth factor receptor 1 (Fgfr1) is mediated by alternative splicing of the juxtamembrane domain. The Journal of biological chemistry 57 11729184
2004 FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity. Journal of cell science 49 15564375
2005 Direct interaction of Rnd1 with FRS2 beta regulates Rnd1-induced down-regulation of RhoA activity and is involved in fibroblast growth factor-induced neurite outgrowth in PC12 cells. The Journal of biological chemistry 48 15738000
2010 An FGF4-FRS2alpha-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos. Stem cells (Dayton, Ohio) 46 19890878
2003 Fibroblast growth factor-2-induced signaling through lipid raft-associated fibroblast growth factor receptor substrate 2 (FRS2). The Journal of biological chemistry 46 12571252
2018 Consistent Amplification of FRS2 and MDM2 in Low-grade Osteosarcoma: A Genetic Study of 22 Cases With Clinicopathologic Analysis. The American journal of surgical pathology 40 30001240
2020 LncRNA ANRIL regulates cell proliferation and migration via sponging miR-339-5p and regulating FRS2 expression in atherosclerosis. European review for medical and pharmacological sciences 37 32141564
2016 Sinapine reverses multi-drug resistance in MCF-7/dox cancer cells by downregulating FGFR4/FRS2α-ERK1/2 pathway-mediated NF-κB activation. Phytomedicine : international journal of phytotherapy and phytopharmacology 37 26969380
2003 EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2. Biological chemistry 37 12974390
2011 FRS2α is essential for the fibroblast growth factor to regulate the mTOR pathway and autophagy in mouse embryonic fibroblasts. International journal of biological sciences 35 21927580
2007 Generation of an Frs2alpha conditional null allele. Genesis (New York, N.Y. : 2000) 35 17868091
2001 Developmental expression patterns of the signaling adapters FRS-2 and FRS-3 during early embryogenesis. Mechanisms of development 33 11335123
2009 The FRS2 family of docking/scaffolding adaptor proteins as therapeutic targets of cancer treatment. Expert opinion on therapeutic targets 32 19456272
2006 K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways. Journal of molecular biology 32 16476447
2006 Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins. The Journal of biological chemistry 32 17145761
2014 The Tyrosine Kinase Adaptor Protein FRS2 Is Oncogenic and Amplified in High-Grade Serous Ovarian Cancer. Molecular cancer research : MCR 31 25368431
2009 FRS2alpha is required for the separation, migration, and survival of pharyngeal-endoderm derived organs including thyroid, ultimobranchial body, parathyroid, and thymus. Developmental dynamics : an official publication of the American Association of Anatomists 31 19235715
2007 ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation. FEBS letters 31 17274988
2001 Multiple effector domains within SNT1 coordinate ERK activation and neuronal differentiation of PC12 cells. The Journal of biological chemistry 31 11278583
1999 Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling. The Journal of biological chemistry 31 10383403
2012 Frs2α enhances fibroblast growth factor-mediated survival and differentiation in lens development. Development (Cambridge, England) 30 23136392
2010 FRS2α regulates Erk levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells. Stem cells (Dayton, Ohio) 30 20652960
2009 Deletion of Frs2alpha from the ureteric epithelium causes renal hypoplasia. American journal of physiology. Renal physiology 28 19741018
2011 Independent roles of Fgfr2 and Frs2alpha in ureteric epithelium. Development (Cambridge, England) 26 21350013
2007 Fibroblast growth factor receptor 1 (FGFR1) tyrosine phosphorylation regulates binding of FGFR substrate 2alpha (FRS2alpha) but not FRS2 to the receptor. Molecular endocrinology (Baltimore, Md.) 25 17901128
2007 FRS2 alpha 2F/2F mice lack carotid body and exhibit abnormalities of the superior cervical sympathetic ganglion and carotid sinus nerve. Developmental biology 25 18177855
2002 FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. The Journal of biological chemistry 25 11877385
2021 Kaempferol alleviates human endothelial cell injury through circNOL12/miR-6873-3p/FRS2 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 33761622
2012 Ureteric morphogenesis requires Fgfr1 and Fgfr2/Frs2α signaling in the metanephric mesenchyme. Journal of the American Society of Nephrology : JASN 24 22282599
2019 miR-200c-3p Suppresses the Proliferative, Migratory, and Invasive Capacities of Nephroblastoma Cells via Targeting FRS2. Biopreservation and biobanking 22 31194576
2018 Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. The Journal of biological chemistry 22 29540482
2001 Xenopus FRS2 is involved in early embryogenesis in cooperation with the Src family kinase Laloo. EMBO reports 22 11463744
2020 Upregulation of lncRNA ZFAS1 promotes lung adenocarcinoma progression by sponging miR-1271-5p and upregulating FRS2. Thoracic cancer 20 32515146
2021 Circular RNA circUBR4 regulates ox-LDL-induced proliferation and migration of vascular smooth muscle cells through miR-185-5p/FRS2 axis. Molecular and cellular biochemistry 19 34159479
2015 Fibroblast growth factor receptor-Frs2α signaling is critical for nephron progenitors. Developmental biology 19 25641696
2011 Role and expression of FRS2 and FRS3 in prostate cancer. BMC cancer 19 22078327
2017 MicroRNA-613 attenuates the proliferation, migration and invasion of Wilms' tumor via targeting FRS2. European review for medical and pharmacological sciences 18 28829507
2013 The Role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of two activity levels of the components of the extracellular signal-regulated kinase (ERK) pathway in the mouse epididymis. Biology of reproduction 18 23782834
2019 Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells 16 30795553
2015 The impact of FGFR1 and FRS2α expression on sorafenib treatment in metastatic renal cell carcinoma. BMC cancer 16 25900027
2014 The docking protein FRS2α is a critical regulator of VEGF receptors signaling. Proceedings of the National Academy of Sciences of the United States of America 16 24706887
2010 Ternary complex formation of EphA4, FGFR and FRS2α plays an important role in the proliferation of embryonic neural stem/progenitor cells. Genes to cells : devoted to molecular & cellular mechanisms 16 20184660
2006 Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells. Oncogene 16 16682955
2020 MiR-140-5p and miR-92a-3p suppress the cell proliferation, migration and invasion and promoted apoptosis in Wilms' tumor by targeting FRS2. European review for medical and pharmacological sciences 15 31957822
2000 Potential involvement of FRS2 in insulin signaling. Endocrinology 15 10650943
2014 Hepatocyte FRS2α is essential for the endocrine fibroblast growth factor to limit the amplitude of bile acid production induced by prandial activity. Current molecular medicine 14 25056539
2002 SNT1/FRS2 mediates germinal vesicle breakdown induced by an activated FGF receptor1 in Xenopus oocytes. The Journal of biological chemistry 14 12082104
2001 SNT-1/FRS2alpha physically interacts with Laloo and mediates mesoderm induction by fibroblast growth factor. Mechanisms of development 14 11731233
2018 Intraocular miR-211 exacerbates pressure-induced cell death in retinal ganglion cells via direct repression of FRS2 signaling. Biochemical and biophysical research communications 13 30131252
2014 The signaling adapter, FRS2, facilitates neuronal branching in primary cortical neurons via both Grb2- and Shp2-dependent mechanisms. Journal of molecular neuroscience : MN 13 25159185
2010 FGF2 promotes Msx2 stimulated PC-1 expression via Frs2/MAPK signaling. Journal of cellular biochemistry 13 20803545
2019 FGF-induced LHX9 regulates the progression and metastasis of osteosarcoma via FRS2/TGF-β/β-catenin pathway. Cell division 12 31788020
2021 LncRNA SNHG6 Promotes Wilms' Tumor Progression Through Regulating miR-429/FRS2 Axis. Cancer biotherapy & radiopharmaceuticals 11 33481659
2014 Structural insights into FRS2α PTB domain recognition by neurotrophin receptor TrkB. Proteins 11 24470253
2000 A novel type I fibroblast growth factor receptor activates mitogenic signaling in the absence of detectable tyrosine phosphorylation of FRS2. The Journal of biological chemistry 11 10748122
2022 Discovery of a small molecule ligand of FRS2 that inhibits invasion and tumor growth. Cellular oncology (Dordrecht, Netherlands) 10 36495366
2021 Long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) regulates fibroblast growth factor receptor substrate 2 (FRS2) by targeting microRNA (miR)-29-3p in hypertrophic scar fibroblasts. Bioengineered 10 34414852
2021 Circ_0002984 Enhances Growth, Invasion, and Migration in PDGF-bb-Induced Vascular Smooth Muscle Cells Through miR-379-5p/FRS2 Axis. Journal of cardiovascular pharmacology 10 34882114
1990 Construction of a FRS1-FRS2 operon encoding the structural genes for the alpha and beta subunits of yeast phenylalanyl-tRNA synthetase and its use in deletion analysis. Nucleic acids research 10 2336390
2019 Myristoylation-Dependent Palmitoylation of the Receptor Tyrosine Kinase Adaptor FRS2α. Biochemistry 9 31184863
2010 Caenorhabditis elegans fibroblast growth factor receptor signaling can occur independently of the multi-substrate adaptor FRS2. Genetics 9 20308281
2003 Genomic organization and comparative sequence analysis of the mouse and human FRS2, FRS3 genes. Molecular biology reports 9 12688531
2015 Trans-Activation between EphA and FGFR Regulates Self-Renewal and Differentiation of Mouse Embryonic Neural Stem/Progenitor Cells via Differential Activation of FRS2α. PloS one 8 26024354
2002 Cell- and receptor isotype-specific phosphorylation of SNT1 by fibroblast growth factor receptor tyrosine kinases. In vitro cellular & developmental biology. Animal 8 12026167
2002 Overexpression of the signaling adapter FRS2 reconstitutes the cell cycle deficit of a nerve growth factor non-responsive TrkA receptor mutant. Journal of neurochemistry 8 12065641
2020 MiR-96 promotes apoptosis of nucleus pulpous cells by targeting FRS2. Human cell 7 32578051
2002 Docking protein SNT1 is a critical mediator of fibroblast growth factor signaling during Xenopus embryonic development. Developmental dynamics : an official publication of the American Association of Anatomists 7 11836786
2017 Thyroid Hormone-Induced Expression of the Hepatic Scaffold Proteins Sestrin2, β-Klotho, and FRS2α in Relation to FGF21-AMPK Signaling. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 6 28895643
2023 Effective fraction of Gualou-Xiebai-Banxia decoction inhibits the apoptosis of myocardial cells induced by ox-LDL via FGF21/FGFR1/βKlotho-FRS2α signal pathway. Journal of ethnopharmacology 5 37595815
2021 Expression of FRS2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: an immunohistochemical analysis of 182 cases with genetic data. Diagnostic pathology 5 34696768
2024 Over-expression of microRNA-145 Elevating Autophagy Activities via Downregulating FRS2 Expression. Combinatorial chemistry & high throughput screening 4 37264620
2023 FRS2 regulated by miR-429 and miR-206 promotes angiogenesis in osteosarcoma. Gene 4 38159618
2019 FRS2α-dependent cell fate transition during endocardial cushion morphogenesis. Developmental biology 4 31669335
2017 Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis. Neuroscience 4 29155277
2023 FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development. Biology open 3 37421147
2008 Cell migration by a FRS2-adaptor dependent membrane relocation of ret receptors. Journal of cellular biochemistry 3 18189271
2025 Shc1 cooperates with Frs2 and Shp2 to recruit Grb2 in FGF-induced lens development. eLife 2 40327534
2023 Characterization of the folding and binding properties of the PTB domain of FRS2 with phosphorylated and unphosphorylated ligands. Archives of biochemistry and biophysics 2 37543351
2022 TRIM44 Promotes Endometrial Carcinoma Progression by Activating the FRS2 Signalling Pathway. Evidence-based complementary and alternative medicine : eCAM 2 36387361