Affinage

FRS2

Fibroblast growth factor receptor substrate 2 · UniProt Q8WU20

Length
508 aa
Mass
57.0 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FRS2 (FRS2alpha) is a lipid-anchored docking protein that nucleates assembly of signaling complexes downstream of receptor tyrosine kinases to drive sustained Ras/ERK and PI3K/Akt activation required for development and growth (PMID:9632781, PMID:11447289). Its PTB domain engages two structurally distinct receptor classes by different mechanisms: it binds the juxtamembrane region of FGFR1 constitutively (phosphorylation-independent, entropy-driven) and the NPXpY motifs of activated TrkA/TrkB (pY490) and RET (pY1062) in a phosphorylation-dependent manner, using adjacent but distinct binding pockets that make these interactions mutually exclusive (PMID:10629055, PMID:11877385, PMID:24470253). Upon receptor activation FRS2alpha is multiply tyrosine-phosphorylated, directly recruiting Grb2 and Shp2 to build a multiprotein complex including Gab1, Sos, and Cbl; the Shp2-binding sites drive sustained ERK and PI3K signaling while Grb2 brings in the E3 ligase Cbl to ubiquitinate the receptor and FRS2alpha as negative feedback (PMID:9632781, PMID:11447289, PMID:11997436). A second feedback layer operates through MAP kinase/ERK1/2-mediated threonine phosphorylation of FRS2alpha, which dampens its own tyrosine phosphorylation and restrains ERK output, proliferation, and anchorage-independent growth (PMID:12419216, PMID:12974390). Membrane localization is conferred by N-myristoylation coupled to palmitoylation at Cys4/Cys5, which targets FRS2alpha to lipid rafts where signaling assembly occurs (PMID:12571252, PMID:31184863). Genetically, FRS2alpha is essential for embryogenesis and FGF-dependent organogenesis, with Shp2-binding sites specifically required for eye/lens induction, cortical neural progenitor expansion, and pharyngeal organ migration (PMID:11447289, PMID:15569927, PMID:16239343, PMID:19235715), and it additionally transduces VEGF receptor signals controlling angiogenesis and lymphangiogenesis and FGFR4 signals controlling bile acid homeostasis (PMID:24706887, PMID:25056539). Persistent FRS2 engagement by oncogenic receptor variants drives transformation, making it a node in RTK-driven cancer (PMID:19103595, PMID:29540482).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 1998 High

    Established that FRS2 functions as a docking protein whose recruitment of both Shp2 and Grb2 is required to convert transient into sustained ERK signaling and drive differentiation.

    Evidence Co-IP, FRS2 point mutagenesis and dominant-negative Shp2 in PC12 differentiation assays

    PMID:9632781

    Open questions at the time
    • Did not resolve which individual tyrosines bind Grb2 versus Shp2
    • Mechanism of receptor engagement not addressed
  2. 1999 High

    Showed FRS2 couples to the NGF receptor TrkA at the same phosphotyrosine as Shc and can functionally reconstitute neuronal differentiation, defining FRS2 as a shared RTK adaptor.

    Evidence cDNA cloning, Co-IP of multiple partners, functional rescue in NGF-nonresponsive TrkA mutant cells

    PMID:10092678

    Open questions at the time
    • Competition with Shc not quantified
    • FGF receptor binding mode not yet contrasted
  3. 1999 Medium

    Identified FRS2 as an anchoring protein for activated atypical PKCs rather than a substrate, expanding its role beyond ERK adaptor functions.

    Evidence Yeast two-hybrid, Co-IP and in vitro kinase assays with constitutively active PKClambda

    PMID:10383403

    Open questions at the time
    • Physiological consequence of aPKC anchoring not defined
    • Single lab
  4. 2000 High

    Resolved the dual binding logic of the PTB domain: constitutive phosphorylation-independent binding to FGFR1 versus phosphotyrosine-dependent binding to TrkA, with FGFR1 able to sequester FRS2.

    Evidence Peptide competition, alanine-scanning mutagenesis, phosphorylation-dependent binding assays

    PMID:10629055

    Open questions at the time
    • Structural basis of the two modes not resolved here
    • In vivo relevance of sequestration untested
  5. 2001 High

    Demonstrated FRS2alpha is essential for FGF signaling and embryogenesis, with distinct tyrosine sites mediating distinct responses, establishing its non-redundant developmental role.

    Evidence Mouse knockout (E7.0-7.5 lethality), MEF assays for MAPK/PI3K/chemotaxis/proliferation, complex assembly analysis

    PMID:11447289

    Open questions at the time
    • Tissue-specific requirements not separable in a global null
    • Site-specific phenotypes only correlative at this stage
  6. 2001 High

    Showed FRS2 docks on RET at pY1062 and that constitutive engagement by oncogenic RET-PTC drives sustained MAPK, while HSCR loss-of-function mutants impair FRS2 binding, linking FRS2 to RET-driven disease.

    Evidence Co-IP, RET Y1062 mutagenesis, oncogenic and loss-of-function mutant panels, MAPK/proliferation assays

    PMID:11360177 PMID:11390647

    Open questions at the time
    • FRS2 selectivity for RAS/MAPK over PI3K only inferred from complex composition
    • Adaptor competition at Y1062 not quantified
  7. 2001 Medium

    Established that an alternatively spliced FGFR1 juxtamembrane VT motif is required for FRS2 binding and ERK activation, linking receptor isoform choice to FRS2 coupling.

    Evidence Co-IP with VT+/VT- isoforms and ERK2 assays

    PMID:11729184

    Open questions at the time
    • Single lab
    • Physiological prevalence of VT- isoforms not assessed
  8. 2001 Medium

    Placed FRS2 in a Src-family kinase (Laloo)-FGFR1 complex required for mesoderm induction and axis formation in vivo.

    Evidence Xenopus overexpression/dominant-negative, Co-IP with Laloo and FGFR1, Ras epistasis, explant assays

    PMID:11463744 PMID:11731233

    Open questions at the time
    • Direct kinase-substrate relationship not fully defined
    • Model-organism context
  9. 2002 High

    Defined a MAP kinase-mediated negative feedback loop: ERK phosphorylates FRS2alpha on threonines to suppress its tyrosine phosphorylation, restraining proliferation and transformation.

    Evidence Threonine site mutagenesis, in vitro kinase assays, soft-agar and migration/proliferation assays

    PMID:12419216 PMID:12974390

    Open questions at the time
    • Stoichiometry and kinetics of feedback in vivo unclear
    • Specific threonines mapped only partially
  10. 2002 High

    Identified Grb2-bridged recruitment of the E3 ligase Cbl as a feedback mechanism ubiquitinating FGFR and FRS2alpha, with redundant downregulation routes.

    Evidence Co-IP of ternary FRS2-Grb2-Cbl complex, ubiquitination assays, FRS2-null cells

    PMID:11997436

    Open questions at the time
    • Identity of redundant downregulation pathway unknown
    • Ubiquitination sites not mapped
  11. 2002 High

    Provided the biophysical basis for dual receptor recognition: enthalpy-driven phosphotyrosine binding to Trk versus entropy-driven phosphorylation-independent binding to FGFR1, with the C-terminal region modulating PTB conformation.

    Evidence Isothermal titration calorimetry, NMR, mutagenesis

    PMID:11877385

    Open questions at the time
    • High-resolution structure of FGFR1-bound state not determined here
    • Functional consequence of C-terminal autoinhibition in cells untested
  12. 2003 Medium

    Localized FRS2 to lipid rafts and showed serine/threonine phosphorylation within rafts (PKC/Src/MEK) suppresses tyrosine phosphorylation, integrating membrane microdomain context with feedback regulation.

    Evidence Lipid raft fractionation, inhibitor studies, Grb2 co-fractionation

    PMID:12571252

    Open questions at the time
    • Mechanism of raft targeting not yet molecular
    • Single lab
  13. 2004 Medium

    Defined FRS2 as the intermediary that recruits and activates Src family kinases to phosphorylate Sprouty2, wiring FRS2 into ERK pathway feedback inhibition.

    Evidence Src inhibitor, mutant cells, Co-IP of Src-Sprouty2, FRS2-dependent Src activation

    PMID:15564375

    Open questions at the time
    • Direct FRS2-Src binding interface not mapped
    • Single lab
  14. 2004 High

    Used allele-specific knock-in mice to show Shp2-binding (not Grb2-binding) sites on FRS2alpha are required for eye/lens induction via ERK and downstream eye-field genes.

    Evidence Frs2alpha 2F/2F vs 4F/4F knock-in mice, IHC, in vivo pERK, marker gene analysis

    PMID:15569927

    Open questions at the time
    • Why Grb2 sites are dispensable here not explained
    • Cell-autonomy not fully resolved
  15. 2005 High

    Extended the Shp2-site requirement to cortical neural progenitor proliferation, distinguishing FRS2-dependent proliferation from FGF2-induced self-renewal.

    Evidence Frs2alpha 2F knock-in mice, BrdU, neurosphere assays, cortical histology

    PMID:16239343

    Open questions at the time
    • Molecular distinction between proliferation and self-renewal pathways unclear
  16. 2005 Medium

    Revealed a non-ERK output: FRS2 binds Rnd1 and, upon Shp2 recruitment displacing Rnd1, modulates RhoA activity to promote neurite outgrowth.

    Evidence Direct binding/pulldown, RhoA activity assays, Rnd1 siRNA, PC12 neurite outgrowth

    PMID:15738000

    Open questions at the time
    • In vivo relevance of Rnd1-RhoA arm untested
    • Single lab
  17. 2007 Medium

    Clarified that the FRS2alpha C-terminal region autoinhibits PTB-FGFR1 binding, relieved by receptor kinase activation, and that Grb2 sites mediate FiRE enhancer activation.

    Evidence Co-IP with kinase-dead/tyrosine FGFR1 mutants, PTB truncations, reporter assay

    PMID:17901128

    Open questions at the time
    • Conformational mechanism of relief not structurally resolved
    • Single lab
  18. 2007 Medium

    Showed FRS2 recruits RET to focal complexes to activate Src/FAK and drive migration, with adaptor competition at Y1062 dictating outcome.

    Evidence Co-IP, focal complex microscopy, Src/FAK assays, RET Y1062/Y981 mutagenesis, migration assays

    PMID:18189271

    Open questions at the time
    • Quantitative competition model not established
    • Single lab
  19. 2007 Medium

    Demonstrated FRS2alpha (via Shp2 sites) is required for migration but not initial specification of pharyngeal-endoderm organs, separating its roles in morphogenesis from cell fate.

    Evidence Frs2alpha 2F/2F mice, staged histology and differentiation marker immunostaining

    PMID:19235715

    Open questions at the time
    • Migration effector pathway downstream of FRS2 not identified
    • Single lab
  20. 2008 Medium

    Established cell-type-specific requirements for FRS2alpha in cardiac outflow tract development, including progenitor expansion and EndMT.

    Evidence Conditional knockout, histology, lineage tracing, immunostaining

    PMID:18832393

    Open questions at the time
    • Receptor(s) upstream in this context not defined
    • Single lab
  21. 2008 Medium

    Showed persistent FRS2 engagement by an oncogenic FGFR2 IIIb Y770F variant is required for enhanced transformation, establishing FRS2 as an oncogenic driver node.

    Evidence FGFR2 mutagenesis (Y770F/L773A), Co-IP, focus formation assays

    PMID:19103595

    Open questions at the time
    • Downstream effectors of the persistent complex not dissected
    • Single lab
  22. 2010 Medium

    Identified EphA4 as a direct FRS2alpha PTB partner and kinase, forming a ternary EphA4-FGFR-FRS2alpha complex that supports neural progenitor proliferation.

    Evidence Yeast two-hybrid, in vitro binding and kinase assays, dominant-negative constructs, NSC proliferation assay

    PMID:20184660

    Open questions at the time
    • In vivo requirement of the ternary complex untested
    • Single lab
  23. 2010 Medium

    Defined a paracrine FRS2alpha-ERK-Cdx2-Bmp4 axis in trophoblast stem cells supporting inner cell mass growth.

    Evidence Frs2alpha-null ES/TS cells, ChIP on Bmp4 promoter, Bmp4 rescue, ERK assays

    PMID:19890878

    Open questions at the time
    • Generalizability beyond TS cells unclear
    • Single lab
  24. 2011 Medium

    Linked FRS2alpha-FGF signaling to autophagy suppression via PI3K/Akt/mTOR, with loss promoting premature cardiac progenitor differentiation.

    Evidence Conditional knockout and Frs2alpha-null MEFs, LC3 assays, PI3K/Akt/mTOR inhibitors

    PMID:21927580 PMID:22207710

    Open questions at the time
    • Direct molecular link between FRS2 and mTOR not mapped
    • Single lab cluster
  25. 2014 High

    Extended FRS2alpha function to VEGF receptor signaling, showing it is required in endothelium for angiogenesis, lymphangiogenesis, and arteriogenesis.

    Evidence Endothelial-specific conditional knockout, in vitro VEGF signaling, in vivo vascular phenotyping

    PMID:24706887

    Open questions at the time
    • Direct VEGFR-FRS2 binding mode not characterized
    • Single lab
  26. 2014 Medium

    Established FRS2alpha as the hepatocyte adaptor required for FGF15/19-FGFR4 repression of Cyp7a1 and bile acid homeostasis.

    Evidence Hepatocyte-specific knockout, Cyp7a1 mRNA quantification, FGFR4 gain/loss-of-function

    PMID:25056539

    Open questions at the time
    • Downstream transcriptional effectors of Cyp7a1 repression not defined
    • Single lab
  27. 2014 High

    Provided structural confirmation of two distinct adjacent PTB binding pockets enabling mutually exclusive FGFR versus Trk engagement.

    Evidence NMR structure of PTB bound to phosphorylated TrkB, binding pocket analysis

    PMID:24470253

    Open questions at the time
    • FGFR-bound structure complementary to TrkB structure not solved
    • Allosteric coupling between pockets unresolved
  28. 2014 Medium

    Showed FRS2 drives neurotrophin-induced neurite outgrowth through both Grb2 and Shp2 pathways, with Grb2 bridging to Gab1/Gab2 and PI3K, and that FRS3 cannot substitute.

    Evidence Adenoviral FRS2 mutant overexpression in primary cortical neurons, neurite quantification, Gab1/Gab2 Co-IP

    PMID:25159185

    Open questions at the time
    • Basis for FRS3 inability not explained
    • Overexpression context
  29. 2019 Medium

    Defined the membrane-anchoring mechanism: coupled N-myristoylation and Cys4/Cys5 palmitoylation are required for plasma membrane localization, with myristoylation a prerequisite for palmitoylation.

    Evidence Palmitoylation assays, G2A/C4A/C5A mutagenesis, fluorescence fluctuation spectroscopy

    PMID:31184863

    Open questions at the time
    • Identity of the palmitoyltransferase unknown
    • Single lab
  30. 2018 Medium

    Showed pharmacological inhibition of FRS2alpha myristoylation suppresses FGFR-driven oncogenic signaling and tumorigenesis, nominating membrane anchoring as a therapeutic target.

    Evidence N-myristoyltransferase inhibitor B13, phosphorylation assays, xenograft model, FGFR inhibitor combination

    PMID:29540482

    Open questions at the time
    • B13 specificity for FRS2 versus other myristoylated proteins not isolated
    • Single lab
  31. 2019 Medium

    Identified FRS2alpha as a developmental-stage-specific controller of EndMT, restraining TGFbeta signaling in a let-7-dependent manner.

    Evidence Inducible endothelial-specific knockout at E7.5 vs E10.5, histological/molecular AV valve analysis

    PMID:31669335

    Open questions at the time
    • Mechanism linking FRS2 loss to let-7/TGFbeta not fully defined
    • Single lab
  32. 2023 Medium

    Characterized the folding pathway and electrostatic, ionic-strength-dependent binding kinetics of the PTB domain for both FGFR1 and TrkB ligands.

    Evidence Equilibrium/kinetic folding and binding assays at varied ionic strength, site-directed mutagenesis

    PMID:37543351

    Open questions at the time
    • Cellular relevance of folding intermediate unknown
    • Single lab
  33. 2025 High

    Refined the lens model: FRS2 and Shp2 act mainly in fiber cell differentiation, and Shc1 collaborates with them to recruit Grb2, defining a partially redundant Grb2-recruitment module.

    Evidence Combinatorial conditional knockouts of Frs2/Shp2/Shc1, MAPK assays, lens phenotyping

    PMID:40327534

    Open questions at the time
    • Quantitative contribution of each adaptor to Grb2 recruitment unresolved
    • Generalizability to other tissues untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the lipid-raft-anchored FRS2alpha integrates the multiple competing inputs (FGFR, Trk, RET, VEGFR, EphA4) into context-specific ERK versus PI3K versus RhoA outputs, and the structural mechanism by which C-terminal autoinhibition and threonine feedback are dynamically tuned, remains unresolved.
  • No full-length FRS2alpha structure in a receptor-bound signaling complex
  • Quantitative model of adaptor competition and feedback dynamics lacking
  • VEGFR and EphA4 binding modes not structurally defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 2
Partners
CBLFGFR1GAB1GRB2PTPN11RETRND1SRC
Complex memberships
EphA4-FGFR-FRS2alpha ternary complexFRS2alpha-Grb2-Cbl complexFRS2alpha-Grb2-Sos1-Shp2 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 FRS2 (FRS2alpha) forms a complex with the N-terminal SH2 domain of Shp2 upon FGF stimulation; the 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 in response to FGF. Shp2 catalytic activity is required for sustained ERK activation and potentiation of FGF-induced differentiation. Co-immunoprecipitation, point mutagenesis of FRS2, dominant-negative Shp2 expression, PC12 differentiation assay Molecular and cellular biology High 9632781
2000 The PTB domains of FRS2alpha and FRS2beta bind directly to a highly conserved juxtamembrane sequence in FGFR1 constitutively (phosphorylation-independent), while binding to TrkA (NGF receptor) at pY490 (NPXpY motif) is phosphorylation-dependent. Thus the same PTB domain recognizes two structurally distinct receptor sequences by different mechanisms. FRS2alpha tyrosine phosphorylation in response to NGF is diminished when a kinase-inactive FGFR1 is overexpressed, indicating FGFR1 can sequester FRS2 away from TrkA. Peptide competition assays, deletion and alanine-scanning mutagenesis, phosphorylation-dependent binding assays, dominant-negative FGFR1 overexpression Molecular and cellular biology High 10629055
1999 FRS2 PTB domain binds TrkA at the same phosphotyrosine residue (Y490) as Shc, suggesting competitive binding. FRS2 also binds Grb2, Crk, SH-PTP-2, p13(suc1), and the SH3 domain of Src. Overexpression of FRS2 in cells expressing a TrkA NGF-nonresponsive mutant reconstitutes NGF-induced cell cycle arrest and neuronal differentiation. cDNA cloning, co-immunoprecipitation, functional reconstitution by overexpression in mutant TrkA cells, differentiation assay The Journal of biological chemistry High 10092678
2001 Targeted disruption of FRS2alpha in mice causes embryonic lethality at E7.0–E7.5. FRS2alpha-deficient fibroblasts show impaired FGF-induced MAP kinase stimulation, PI3K activation, chemotaxis, and cell proliferation. Tyrosine-phosphorylated FRS2alpha assembles a multiprotein complex including Gab1. Different tyrosine phosphorylation sites on FRS2alpha mediate distinct FGF-induced biological responses. Gene knockout (homologous recombination), MEF functional assays (MAPK, PI3K, chemotaxis, proliferation), multiprotein complex assembly analysis Proceedings of the National Academy of Sciences of the United States of America High 11447289
2001 The FRS2 PTB domain binds RET at pY1062, the same residue that binds Shc. FRS2-RET binding is ligand-dependent for normal RET but constitutive for oncogenic RET-PTC forms, leading to constitutive FRS2 tyrosine phosphorylation and sustained MAP kinase activation. HSCR-associated loss-of-function RET mutants show impaired FRS2 binding and reduced MAP kinase activation. Co-immunoprecipitation, site-directed mutagenesis of RET (Y1062), cell proliferation and MAP kinase assays Molecular and cellular biology High 11390647
2001 The FRS2 docking site on RET is pY1062; SNT/FRS2 is associated with GRB2 but not GAB1 upon RET activation (unlike Shc which associates with both GRB2 and GAB1), indicating FRS2 selectively activates RAS/MAPK but not PI3K/AKT downstream of RET. Site-directed mutagenesis of RET, co-immunoprecipitation, comparison of Shc vs FRS2 complexes Oncogene Medium 11360177
2002 Grb2 bound to tyrosine-phosphorylated FRS2alpha recruits the E3 ubiquitin ligase Cbl through Grb2's SH3 domains, forming a ternary FRS2alpha–Grb2–Cbl complex that ubiquitinates FGFR and FRS2alpha in response to FGF, thereby attenuating FGF receptor signaling. FRS2alpha-null cells show only partial impairment of receptor downregulation, indicating redundant mechanisms. Co-immunoprecipitation, ubiquitination assays, FRS2alpha-null cells Proceedings of the National Academy of Sciences of the United States of America High 11997436
2002 FRS2alpha is phosphorylated by MAP kinase on multiple threonine residues upon FGF stimulation (and also by insulin, EGF, PDGF without FRS2alpha tyrosine phosphorylation). Preventing FRS2alpha threonine phosphorylation results in constitutive tyrosine phosphorylation, enhanced ERK activation, cell migration, proliferation, and anchorage-independent growth, revealing a MAPK-mediated negative feedback loop controlling FRS2alpha activity. Threonine phosphorylation site mutagenesis, in vitro kinase assays, soft-agar colony formation, cell proliferation and migration assays Molecular cell High 12419216
2001 Alternative splicing of the FGFR1 juxtamembrane region (inclusion of VT motif) is required for FRS2 interaction with FGFR1; VT-minus isoforms cannot bind FRS2, accounting for their inability to activate ERK2. Co-immunoprecipitation with VT+ and VT- isoforms, ERK2 phosphorylation assays The Journal of biological chemistry Medium 11729184
2002 The FRS2alpha PTB domain uses thermodynamically distinct binding modes for TrkA/TrkB (enthalpy-driven, phosphotyrosine-dependent NPXpY recognition) versus FGFR1 (entropy-driven, phosphorylation-independent). NMR analysis shows the unstructured region C-terminal to the PTB domain alters PTB conformation and binding; disruption of the beta8-strand weakens FGFR interaction. Isothermal titration calorimetry, NMR spectroscopy, mutagenesis The Journal of biological chemistry High 11877385
2003 FRS2 is localized exclusively to lipid raft membrane microdomains in vitro and in vivo. Serine/threonine phosphorylation of FRS2 within lipid rafts (mediated by PKC, Src family kinases, MEK1/2) indirectly reduces FRS2 tyrosine phosphorylation levels. Grb2 is recruited to lipid rafts during FGF2 signaling. Lipid raft fractionation, phosphorylation assays, inhibitor studies (PKC, Src, MEK), Grb2 co-fractionation The Journal of biological chemistry Medium 12571252
2003 FRS2 undergoes ERK1/2-mediated serine/threonine phosphorylation in response to EGF and FGF stimulation. ERK1/2 constitutively associates with the central portion of FRS2, while the C-terminal region is the ERK2 substrate. Inhibiting ERK1/2 enhances FRS2 tyrosine phosphorylation, demonstrating a negative feedback loop where activated ERK1/2 phosphorylates FRS2 to downregulate its tyrosine phosphorylation. MEK inhibitor (U0126), co-immunoprecipitation of ERK with FRS2, in vitro kinase assays, SDS-PAGE mobility shift Biological chemistry Medium 12974390
2004 FGF receptor-mediated Sprouty2 phosphorylation on Y55 requires FRS2 as an intermediary; FRS2 recruits and activates Src family kinases, which then directly phosphorylate Sprouty2. Phospho-Sprouty2 forms a complex with Src and inhibits ERK pathway activation. Src inhibitor, mutant cell lines, co-immunoprecipitation of Src–Sprouty2 complex, FRS2-dependent Src activation assays Journal of cell science Medium 15564375
2004 Shp2-binding tyrosine sites on FRS2alpha are critical for retinal and lens induction in vivo: Frs2alpha(2F/2F) mice (Shp2-binding sites mutated) develop anophthalmia/microphthalmia with reduced pERK and decreased Pax6, Six3, Chx10 and Bmp4 expression, while Frs2alpha(4F/4F) (Grb2-binding sites mutated) mice show normal early eye development. Knock-in point mutation mice, immunohistochemistry, in vivo ERK activation measurement, marker gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 15569927
2005 FRS2alpha directly associates with Rnd1 (and FRS2beta does as well); FRS2beta interaction with Rnd1 suppresses Rnd1's inhibitory effect on RhoA. Upon FGFR1 activation and FRS2beta tyrosine phosphorylation, Shp2 is recruited to FRS2beta and displaces Rnd1; liberated Rnd1 then inhibits RhoA activity to promote neurite outgrowth. Direct protein binding (pulldown/Co-IP), FGFR1 phosphorylation assays, RhoA activity assays, siRNA knockdown of Rnd1, neurite outgrowth assay in PC12 cells The Journal of biological chemistry Medium 15738000
2005 Disruption of Shp2-binding sites on FRS2alpha (Frs2alpha(2F)) in mice causes severe cortical development defects due to loss of intermediate progenitor cells. FRS2alpha is essential for FGF2-responsive neural progenitor cell proliferation but not for self-renewal capacity after FGF2 stimulation. Knock-in point mutation mice, BrdU labeling, neurosphere assay, histological analysis of cortex Proceedings of the National Academy of Sciences of the United States of America High 16239343
1999 FRS2 associates with atypical protein kinase C lambda (PKClambda) in Swiss 3T3 cells stimulated with bFGF; PKC zeta also binds FRS2. The interaction is likely direct (yeast two-hybrid). Activated PKClambda (constitutively active A120E mutant) shows greater than 2-fold higher FRS2 binding than wild-type. In vitro kinase assays show FRS2 is not a substrate for PKClambda or PKCzeta, suggesting FRS2 acts as an anchoring/targeting protein for activated atypical PKCs at the plasma membrane. Co-immunoprecipitation, yeast two-hybrid, in vitro kinase assay, constitutively active PKClambda mutant The Journal of biological chemistry Medium 10383403
2007 FRS2alpha is required for separation, migration, and survival of pharyngeal-endoderm-derived organs (thyroid, ultimobranchial body, parathyroid, thymus) in Frs2alpha(2F/2F) mice; organ-specific differentiation markers are initially expressed normally, indicating FRS2alpha mediates migration but not initial specification of these organs. Knock-in point mutation mice (Shp2-binding site), histology, immunostaining for differentiation markers at sequential developmental stages Developmental dynamics Medium 19235715
2008 FRS2alpha ablation in mesodermal outflow tract progenitors (second heart field) impairs their expansion, causing outflow tract misalignment/hypoplasia, and also causes defective endothelial-to-mesenchymal transition and impaired neural crest recruitment, resulting in outflow tract septation defects. Conditional knockout using Cre/loxP, histology, lineage tracing, immunostaining Development Medium 18832393
2008 FRS2alpha loss-of-function FGFR2 IIIb C3 variant (Y770F mutation) causes persistent FRS2 binding to FGFR2 IIIb, enhanced FRS2 tyrosine phosphorylation, and increased transforming activity. FRS2 binding to FGFR2 IIIb is required for Y770F-mediated enhanced transformation, establishing that persistent FRS2 engagement drives oncogenic signaling. Site-directed mutagenesis of FGFR2 (Y770F, L773A), Co-IP of FRS2–FGFR2 complex, focus formation/transformation assays The Journal of biological chemistry Medium 19103595
2010 EphA4 directly interacts with the FRS2alpha PTB domain upon phosphorylation of the EphA4 juxtamembrane domain; EphA4 directly phosphorylates FRS2alpha in vitro. A ternary complex of EphA4, FGFR, and FRS2alpha forms, with FRS2alpha and EphA4 binding to different regions of the FGFR juxtamembrane domain simultaneously. Dominant-negative EphA4 or truncated FRS2alpha lacking tyrosine phosphorylation sites inhibit ligand-dependent proliferation of embryonic neural stem/progenitor cells. Yeast two-hybrid, in vitro binding assay, in vitro kinase assay, dominant-negative constructs, neural stem cell proliferation assay Genes to cells Medium 20184660
2010 FRS2alpha mediates FGF4-induced ERK activation in trophoblast stem cells to enhance Cdx2 expression; Cdx2 binds an FGF4-responsive enhancer in the Bmp4 promoter, driving Bmp4 production. Exogenous Bmp4 rescues defective growth of Frs2alpha-null inner cell mass, establishing a paracrine FRS2alpha–ERK–Cdx2–Bmp4 axis. Frs2alpha-null ES/TS cell culture, ChIP for Cdx2 on Bmp4 promoter, Bmp4 rescue experiment, ERK phosphorylation assays Stem cells Medium 19890878
2011 FRS2alpha-mediated FGF signaling suppresses autophagy through the PI3K/Akt/mTOR pathway in mouse embryonic fibroblasts. Loss of FRS2alpha increases autophagy and promotes premature differentiation of cardiac progenitor cells. Frs2alpha conditional knockout in heart progenitors, embryoid body culture, autophagy markers (LC3), PI3K/Akt/mTOR inhibitor studies in Frs2alpha-null MEFs Circulation research Medium 22207710
2011 FRS2alpha-mediated FGF signaling activates mTOR via PI3K/Akt and suppresses autophagy in MEFs; the PI3K/Akt–mTOR axis is the downstream mediator of FGF's autophagy suppression. Frs2alpha-null MEFs, PI3K/Akt/mTOR inhibitor studies, autophagy marker assays (LC3 conversion) International journal of biological sciences Medium 21927580
2001 Xenopus FRS2 (xFRS2) is tyrosine-phosphorylated in early embryos; overexpression of unphosphorylatable xFRS2 interferes with FGF-dependent mesoderm formation. Src family kinase Laloo binds xFRS2, promotes its tyrosine phosphorylation, and both associate with Xenopus FGFR1, placing FRS2 in a Laloo–FGFR1 signaling complex required for mesoderm induction. Xenopus overexpression/dominant-negative experiments, Co-immunoprecipitation of xFRS2 with Laloo and FGFR1, tyrosine phosphorylation assay EMBO reports Medium 11463744
2001 Xenopus SNT-1/FRS2alpha induces mesoderm in ectodermal explants, synergizes with FGF, and requires Ras activity; dominant-inhibitory SNT-1 blocks FGF-mediated mesoderm induction and disrupts axis formation in vivo. SNT-1 physically associates with Src-like kinase Laloo, and SNT-1 activity is required for Laloo-induced mesoderm induction. Xenopus embryo explant assay, dominant-negative constructs, co-immunoprecipitation, Ras inhibition Mechanisms of development Medium 11731233
2002 Xenopus FRS2 (XFRS2) is essential for FGF receptor-induced oocyte maturation (germinal vesicle breakdown). Co-expression of activated XFGFR1 and XFRS2 requires MEK activity (not needed for progesterone-induced GVBD) and PI3K activity for H1 kinase activation at metaphase II. Sprouty2 acts upstream of or parallel to Raf (downstream of Ras) to inhibit XFGFR1/XFRS2-induced MAPK activation and GVBD. Xenopus oocyte microinjection, dominant-negative kinase suppressor of Ras, PI3K inhibitor (LY294002), GVBD and H1 kinase assays The Journal of biological chemistry Medium 12082104
2007 FRS2 selectively recruits RET to focal complexes/membrane foci, activating Src family kinases and FAK to drive cell migration. Competitive recruitment of FRS2 vs. other adaptors to Y1062 in RET determines migration outcome; Src activation requires direct interaction at Y981, and both Y1062 (FRS2) and Y981 (Src) signals act in concert to regulate migration. Co-immunoprecipitation, focal complex localization by microscopy, Src/FAK activation assays, RET mutagenesis (Y1062, Y981) Journal of cellular biochemistry Medium 18189271
2014 FRS2alpha plays a critical role in VEGF receptor signaling: in vitro, FRS2alpha regulates VEGF-A and VEGF-C-dependent ERK activation and endothelial cell migration/proliferation; in vivo, endothelial-specific deletion of FRS2alpha profoundly impairs postnatal vascular development, angiogenesis, lymphangiogenesis, and arteriogenesis. Endothelial-specific conditional knockout (Cre/loxP), in vitro VEGF signaling assays, in vivo angiogenesis/lymphangiogenesis phenotyping Proceedings of the National Academy of Sciences of the United States of America High 24706887
2014 The FRS2alpha PTB domain has two adjacent but distinct binding pockets: one for the non-phosphorylated FGFR juxtamembrane region and one for phosphorylated TrkA/TrkB (NPXpY), enabling mutually exclusive interaction with each receptor class. NMR structure of FRS2alpha PTB bound to phosphorylated TrkB is reported. NMR structure determination, binding pocket analysis Proteins High 24470253
2019 FRS2alpha is N-myristoylated and also palmitoylated at cysteines 4 and 5. Mutation of C4/C5 impairs plasma membrane localization. Abolishing myristoylation (G2A mutation) also abrogates palmitoylation, indicating coupled myristoylation-dependent palmitoylation; signaling defects of the G2A mutant may thus be due to loss of palmitoylation rather than myristoylation alone. Palmitoylation assays, site-directed mutagenesis (C4A/C5A, G2A), fluorescence fluctuation spectroscopy (plasma membrane localization quantification) Biochemistry Medium 31184863
2018 Loss of FRS2alpha myristoylation (using N-myristoyltransferase inhibitor B13) suppresses FGF/FGFR-mediated oncogenic signaling, inhibits FGF10-induced tumorigenesis, and reduces PI3K/MAPK signaling downstream of both wild-type and drug-resistant FGFR mutants. B13 inhibits FRS2alpha phosphorylation and mildly alters its plasma membrane localization. N-myristoyltransferase inhibitor (B13), FRS2alpha phosphorylation assays, xenograft tumor model, cell proliferation/migration assays, combination with FGFR inhibitor The Journal of biological chemistry Medium 29540482
2007 FGFR1 tyrosine autophosphorylation is required for optimal binding to full-length FRS2alpha but not to FRS2beta; the PTB domain of FRS2alpha alone binds FGFR1 constitutively, indicating the C-terminal region of FRS2alpha inhibits PTB–FGFR1 interaction that is relieved by receptor kinase activation. The Grb2-binding sites of FRS2alpha are essential for mediating FGFR1 signals to activate the FiRE enhancer. Co-immunoprecipitation in mammalian cells with recombinant proteins, FGFR1 kinase-dead and tyrosine substitution mutants, PTB domain truncation constructs, FiRE enhancer reporter assay Molecular endocrinology Medium 17901128
2014 FRS2 promotes neurotrophin-induced neurite outgrowth and branching in primary cortical neurons via both Grb2- and Shp2-dependent pathways. FRS2 binds Gab1 and Gab2 through Grb2, providing an indirect route to PI3K and Shp2. Loss of Shp2 binding reduces BDNF-induced MAPK activation; loss of either Grb2 or Shp2 binding impairs neuronal growth. FRS3 overexpression does not stimulate neuronal growth. Recombinant adenovirus overexpression of FRS2 mutants, primary cortical neuron culture, neurite outgrowth quantification, Co-IP of Gab1/Gab2 complexes Journal of molecular neuroscience Medium 25159185
2019 FRS2α deletion in endothelial cells induces endothelial-to-mesenchymal transition (EndMT) by activating TGFβ signaling in a miRNA let-7-dependent manner in adult endothelium; during embryonic AV cushion morphogenesis early Frs2α deletion impairs EndMT in AV cushions, while late deletion (E10.5) has no effect, identifying FRS2α as a developmental stage-specific controller of cell fate transition. Inducible endothelial-specific conditional knockout (FRS2αiECKO at E7.5 vs E10.5), histological and molecular analysis of AV valves Developmental biology Medium 31669335
2000 FRS2 is phosphorylated by the insulin receptor (IR) in vitro using purified IR; insulin stimulates tyrosine phosphorylation of endogenous FRS2 in PC12/IR cells and promotes FRS2–Shp2 complex formation. FRS2 was isolated as a potential IR substrate by yeast two-hybrid screening with the Shp2 SH2 domain dependent on active IR. Yeast two-hybrid (Shp2 SH2 domain bait, IR-dependent), in vitro IR kinase assay with GST-FRS2, Co-immunoprecipitation in PC12/IR cells Endocrinology Low 10650943
2014 FRS2α in hepatocytes is required for FGF15/FGF19-FGFR4 signaling to repress Cyp7a1 expression and limit bile acid production after prandial activity. Ablation of hepatocyte Frs2α alleles abolishes FGFR4-mediated Cyp7a1 regulation. Hepatocyte-specific Frs2α conditional knockout, Cyp7a1 mRNA quantification, FGFR4 gain/loss-of-function experiments Current molecular medicine Medium 25056539
2025 FRS2 and Shp2 deletion primarily impairs later lens vesicle development (fiber cell differentiation) rather than lens induction. Shc1 is phosphorylated at Grb2-binding sites downstream of FGF signaling; Shc1 deletion exacerbates the lens vesicle defect caused by Frs2 and Shp2 deletion, establishing Shc1 as a collaborator with Frs2 and Shp2 in recruiting Grb2 to the FGF signaling complex. Conditional knockout of Frs2, Shp2, Shc1 individually and in combination, MAPK signaling assays, lens developmental phenotype analysis eLife High 40327534
2023 The FRS2 PTB domain folds via a mechanism involving an intermediate; binding to unphosphorylated FGFR1 peptide and phosphorylated TrkB peptide is electrostatic in nature (modulated by ionic strength). Site-directed mutagenesis identified specific residues involved in early and late binding events for each ligand. Equilibrium and kinetic folding assays, kinetic binding experiments at varied ionic strengths, site-directed mutagenesis Archives of biochemistry and biophysics Medium 37543351

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 287 10629055
1998 Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Molecular and cellular biology 283 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 253 11447289
2008 Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer science 203 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 191 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 132 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 114 11390647
2006 Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development. Development (Cambridge, England) 107 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 74 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 64 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 62 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 60 19103595
2008 Frs2alpha-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis. Development (Cambridge, England) 59 18832393
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
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 50 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 39 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 34 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
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
2018 Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. The Journal of biological chemistry 23 29540482
2019 miR-200c-3p Suppresses the Proliferative, Migratory, and Invasive Capacities of Nephroblastoma Cells via Targeting FRS2. Biopreservation and biobanking 22 31194576
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
2015 The impact of FGFR1 and FRS2α expression on sorafenib treatment in metastatic renal cell carcinoma. BMC cancer 17 25900027
2019 Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells 16 30795553
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
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 11 34882114
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
2019 Myristoylation-Dependent Palmitoylation of the Receptor Tyrosine Kinase Adaptor FRS2α. Biochemistry 10 31184863
2010 Caenorhabditis elegans fibroblast growth factor receptor signaling can occur independently of the multi-substrate adaptor FRS2. Genetics 10 20308281
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
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 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
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 7 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 6 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
2008 Cell migration by a FRS2-adaptor dependent membrane relocation of ret receptors. Journal of cellular biochemistry 4 18189271
2023 FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development. Biology open 3 37421147
2025 Shc1 cooperates with Frs2 and Shp2 to recruit Grb2 in FGF-induced lens development. eLife 2 40327534
2024 Circ_0004872 deficiency attenuates ox-LDL-induced vascular smooth muscle cell dysfunction by miR-424-5p-dependent regulation of FRS2. Molecular and cellular biochemistry 2 38376663
2023 Expression of fibroblast growth factor receptor substrate 2 (FRS2) in primary retroperitoneal liposarcoma and its clinical implications. European review for medical and pharmacological sciences 2 37458641
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
2022 miR-338-3p acts as a tumor suppressor in lung squamous cell carcinoma by targeting FGFR2/FRS2. Cancer pathogenesis and therapy 2 38328402

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