Gene Symbol: Frs2
Description: fibroblast growth factor receptor substrate 2
Alias: 4732458E18, C330018A15Rik, Frs2alpha, SNT1, fibroblast growth factor receptor substrate 2, FGFR substrate 2, FGFR-signaling adaptor SNT, FRS2-alpha, SNT-1, suc1-associated neurotrophic factor target 1
Species: mouse
Products:     Frs2

Top Publications

  1. Gotoh N, Laks S, Nakashima M, Lax I, Schlessinger J. FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts. FEBS Lett. 2004;564:14-8 pubmed
    b>FRS2alpha and FRS2beta, two members of the FRS2 family of docking proteins, become tyrosine phosphorylated in response to fibroblast growth factor (FGF) or nerve growth factor (NGF) stimulation...
  2. Kouhara H, Hadari Y, Spivak Kroizman T, Schilling J, Bar Sagi D, Lax I, et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell. 1997;89:693-702 pubmed
    ..In this report, we describe the purification, cloning, and characterization of a novel protein, designated FRS2, that is tyrosine phosphorylated and binds to Grb2/Sos in response to FGF or NGF stimulation...
  3. Hadari Y, Kouhara H, Lax I, Schlessinger J. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol Cell Biol. 1998;18:3966-73 pubmed
    b>FRS2 is a lipid-anchored docking protein that plays an important role in linking fibroblast growth factor (FGF) and nerve growth factor receptors with the Ras/mitogen-activated protein (MAP) kinase signaling pathway...
  4. Gotoh N, Ito M, Yamamoto S, Yoshino I, Song N, Wang Y, et al. Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina. Proc Natl Acad Sci U S A. 2004;101:17144-9 pubmed
    ..FGF signaling has been implicated in this signal exchange. The docking protein FRS2alpha is a major mediator of FGF signaling by providing a link between FGF receptors (FGFRs) and a variety of ..
  5. Kameda Y, Ito M, Nishimaki T, Gotoh N. FRS2 alpha 2F/2F mice lack carotid body and exhibit abnormalities of the superior cervical sympathetic ganglion and carotid sinus nerve. Dev Biol. 2008;314:236-47 pubmed publisher
    The docking protein FRS2 alpha is an important mediator of fibroblast growth factor (FGF)-induced signal transduction, and functions by linking FGF receptors (FGFRs) to a variety of intracellular signaling pathways...
  6. Ong S, Guy G, Hadari Y, Laks S, Gotoh N, Schlessinger J, et al. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol Cell Biol. 2000;20:979-89 pubmed
    ..The two members of the FRS2 family, FRS2alpha and FRS2beta, are structurally very similar...
  7. Ridyard M, Robbins S. Fibroblast growth factor-2-induced signaling through lipid raft-associated fibroblast growth factor receptor substrate 2 (FRS2). J Biol Chem. 2003;278:13803-9 pubmed
    ..Herein, we show that this protein is the signaling adaptor FRS2 and that it is localized exclusively to lipid rafts in vitro and in vivo...
  8. Zhang Y, McKeehan K, Lin Y, Zhang J, Wang F. Fibroblast growth factor receptor 1 (FGFR1) tyrosine phosphorylation regulates binding of FGFR substrate 2alpha (FRS2alpha) but not FRS2 to the receptor. Mol Endocrinol. 2008;22:167-75 pubmed
    ..The FGFR substrate 2 (FRS2) family consists of two members, FRS2alpha and FRS2beta, and has been shown to recruit multiple ..
  9. Gotoh N. Control of stemness by fibroblast growth factor signaling in stem cells and cancer stem cells. Curr Stem Cell Res Ther. 2009;4:9-15 pubmed
    ..pathway initiated at the FGF receptors leads to the activation of Ras/ERK pathways via the control center FRS2alpha. Recent emerging evidence suggests that the FGF-ERK axis controls stemness via multiple modes of action...

More Information


  1. Burgar H, Burns H, Elsden J, Lalioti M, Heath J. Association of the signaling adaptor FRS2 with fibroblast growth factor receptor 1 (Fgfr1) is mediated by alternative splicing of the juxtamembrane domain. J Biol Chem. 2002;277:4018-23 pubmed
    ..b>FRS2 is an adaptor protein that links FGFRs to the mitogen-activated protein kinase signaling pathway...
  2. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A. FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proc Natl Acad Sci U S A. 2002;99:6684-9 pubmed
    ..Here, we demonstrate that Grb2 bound to tyrosine-phosphorylated FRS2 alpha forms a ternary complex with Cbl by means of its Src homology 3 domains resulting in the ubiquitination of ..
  3. Madakashira B, Kobrinski D, Hancher A, Arneman E, Wagner B, Wang F, et al. Frs2? enhances fibroblast growth factor-mediated survival and differentiation in lens development. Development. 2012;139:4601-12 pubmed publisher
    ..Additionally, within the lens, only Fgfrs activate the signal transduction molecule Frs2?. Loss of Frs2? in the lens significantly increases apoptosis and decreases phosphorylation of both Erk1/2 and Akt...
  4. Lin Y, Zhang J, Zhang Y, Wang F. Generation of an Frs2alpha conditional null allele. Genesis. 2007;45:554-9 pubmed
    ..FGF receptor substrate 2 alpha (FRS2alpha) is an adaptor protein that recruits downstream substrates to the FGF receptor (FGFR) tyrosine kinase...
  5. Hoch R, Soriano P. Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development. Development. 2006;133:663-73 pubmed
    ..Biochemical studies have implicated Fgf receptor-specific substrates (Frs2, Frs3) as the principal mediators of Fgfr1 signal transduction to the MAPK and PI3K pathways...
  6. Yamamoto S, Yoshino I, Shimazaki T, Murohashi M, Hevner R, Lax I, et al. Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells. Proc Natl Acad Sci U S A. 2005;102:15983-8 pubmed
    ..The docking protein FRS2alpha is a major mediator of signaling by means of FGFs and neurotrophins...
  7. Gotoh N, Manova K, Tanaka S, Murohashi M, Hadari Y, Lee A, et al. The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development. Mol Cell Biol. 2005;25:4105-16 pubmed
    The docking protein FRS2alpha is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2alpha in vivo remains unknown...
  8. McDougall K, Kubu C, Verdi J, Meakin S. Developmental expression patterns of the signaling adapters FRS-2 and FRS-3 during early embryogenesis. Mech Dev. 2001;103:145-8 pubmed
    Two fibroblast growth factor (FGF) receptor substrates (FRS2 and FRS3) are involved in downstream signaling from activated FGF receptors and neurotrophin-activated Trk receptors...
  9. Melillo R, Santoro M, Ong S, Billaud M, Fusco A, Hadari Y, et al. Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Mol Cell Biol. 2001;21:4177-87 pubmed
    ..In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET...
  10. Hadari Y, Gotoh N, Kouhara H, Lax I, Schlessinger J. Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways. Proc Natl Acad Sci U S A. 2001;98:8578-83 pubmed
    The docking protein FRS2 alpha has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs)...
  11. Lax I, Wong A, Lamothe B, Lee A, Frost A, Hawes J, et al. The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Mol Cell. 2002;10:709-19 pubmed
    The docking protein FRS2alpha functions as a major mediator of signaling by FGF and NGF receptors...
  12. Avery A, Figueroa C, Vojtek A. UNC-51-like kinase regulation of fibroblast growth factor receptor substrate 2/3. Cell Signal. 2007;19:177-84 pubmed
    ..b>FRS2/3 are homologs that function as adaptor proteins to mediate signaling of multiple receptor tyrosine kinases...
  13. Zhang Y, Lin Y, Bowles C, Wang F. Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent release of Cks1 from FGFR substrate 2. J Biol Chem. 2004;279:55348-54 pubmed
    ..which triggers ubiquitination and degradation of p27(Kip1), associates with the unphosphorylated form of FGFR substrate 2 (FRS2), an adaptor protein that is phosphorylated by FGFR kinases and recruits downstream signaling molecules...
  14. Sims Lucas S, Cullen McEwen L, Eswarakumar V, Hains D, Kish K, Becknell B, et al. Deletion of Frs2alpha from the ureteric epithelium causes renal hypoplasia. Am J Physiol Renal Physiol. 2009;297:F1208-19 pubmed publisher
    ..Fibroblast growth factor receptor substrate 2alpha (Frs2alpha) is a major docking protein for Fgfr2 with downstream targets including Ets variant (Etv) 4 and Etv5 in other ..
  15. Wang Y, Wang F, Sun T, Trostinskaia A, Wygle D, Puscheck E, et al. Entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Dev Dyn. 2004;231:72-87 pubmed
    ..We found that the MAPK pathway protein set consisting of the following gene products was present: FRS2 alpha, GRB2, GAB1, SOS1, Ha-ras, Raf1/RafB, MEK1,2,5, MAPK/ERK1,2, MAPK/ERK5, and RSK1,2,3 (see abbreviations)...
  16. Tomasovic A, Traub S, Tikkanen R. Molecular networks in FGF signaling: flotillin-1 and cbl-associated protein compete for the binding to fibroblast growth factor receptor substrate 2. PLoS ONE. 2012;7:e29739 pubmed publisher
    b>Fibroblast growth factor receptor substrate 2 (FRS2?) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases...
  17. Zhang J, Lin Y, Zhang Y, Lan Y, Lin C, Moon A, et al. Frs2alpha-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis. Development. 2008;135:3611-22 pubmed publisher
    ..Here, we report that FRS2alpha (FRS2), an adaptor protein that links FGF receptor kinases to multiple signaling pathways, mediates crucial ..
  18. Ozaki K, Miyazaki S, Tanimura S, Kohno M. Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms. J Cell Sci. 2005;118:5861-71 pubmed
    ..effect on ERK activation through its highly effective ability to suppress the association of Grb2-Sos1 complex with FRS2. The cooperative interactions observed among Sprouty isoforms could represent an advanced system that functions to ..
  19. Ono K, Kita T, Sato S, O Neill P, Mak S, Paschaki M, et al. FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation. PLoS Genet. 2014;10:e1004118 pubmed publisher
    ..Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase...
  20. Sims Lucas S, Cusack B, Eswarakumar V, Zhang J, Wang F, Bates C. Independent roles of Fgfr2 and Frs2alpha in ureteric epithelium. Development. 2011;138:1275-80 pubmed publisher
    ..line (Fgfr2(UB-/-)) develop severe ureteric branching defects; however, ureteric deletion of fibroblast growth factor receptor substrate 2? (Frs2?), a key docking protein that transmits fibroblast growth factor receptor intracellular ..
  21. Garcia C, Huang J, Madakashira B, Liu Y, Rajagopal R, Dattilo L, et al. The function of FGF signaling in the lens placode. Dev Biol. 2011;351:176-85 pubmed publisher
    ..Since the expression of proteins required for lens formation was not altered in the knockout placode cells, we can conclude that FGF signaling from the optic vesicle is not required for lens induction. ..
  22. Zhang Y, Zhang J, Lin Y, Lan Y, Lin C, Xuan J, et al. Role of epithelial cell fibroblast growth factor receptor substrate 2alpha in prostate development, regeneration and tumorigenesis. Development. 2008;135:775-84 pubmed publisher
    ..FGF receptor substrate 2alpha (FRS2alpha) is an FGFR interactive adaptor protein that links multiple signaling pathways to the activated FGFR kinase...
  23. Lim Y, Low B, Lim J, Wong E, Guy G. Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling. J Biol Chem. 1999;274:19025-34 pubmed
    b>FRS2 is a docker protein that recruits signaling proteins to the plasma membrane in fibroblast growth factor signal transduction...
  24. Ranzi V, Meakin S, Miranda C, Mondellini P, Pierotti M, Greco A. The signaling adapters fibroblast growth factor receptor substrate 2 and 3 are activated by the thyroid TRK oncoproteins. Endocrinology. 2003;144:922-8 pubmed
    ..In this paper, we investigate the role of FRS2 and FRS3, two related adapter proteins activated by fibroblast growth factor and NTRK1 receptors, in the signaling ..
  25. Di Giovanni V, Walker K, Bushnell D, Schaefer C, Sims Lucas S, Puri P, et al. Fibroblast growth factor receptor-Frs2α signaling is critical for nephron progenitors. Dev Biol. 2015;400:82-93 pubmed publisher
    ..studies using transgenic Pax3cre mice have revealed roles for fibroblast growth factor receptors (Fgfrs) and Fgfr substrate 2α (Frs2α) signaling in early metanephric mesenchyme patterning and in ureteric morphogenesis...
  26. Huang Y, Hamana T, Liu J, Wang C, An L, You P, et al. Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment. J Biol Chem. 2015;290:17753-61 pubmed publisher
    ..FGFR2 signaling mediated by FGFR substrate 2α (FRS2α) is indispensable for formation and maintenance of prostaspheres derived from P63(+) P-bSCs...
  27. Li X, Brunton V, Burgar H, Wheldon L, Heath J. FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity. J Cell Sci. 2004;117:6007-17 pubmed
    ..This event requires the presence of the signalling adaptor fibroblast growth factor receptor substrate 2 (FRS2). The phosphorylation of hSpry2 is therefore mediated by an intermediate kinase...
  28. Zhang J, Chang J, Huang Y, Lin X, Luo Y, Schwartz R, et al. The FGF-BMP signaling axis regulates outflow tract valve primordium formation by promoting cushion neural crest cell differentiation. Circ Res. 2010;107:1209-19 pubmed publisher
    ..The results demonstrate a novel mechanism by which the FGF-BMP signaling axis regulates formation of OFT valve primordia by controlling smooth muscle differentiation of cushion NCCs. ..
  29. Zhang J, Liu J, Huang Y, Chang J, Liu L, McKeehan W, et al. FRS2?-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity. Circ Res. 2012;110:e29-39 pubmed publisher
    ..Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2? (Frs2?) in heart progenitor cells, we demonstrate that disruption of FGF signaling leads to premature differentiation of ..
  30. White J, Auerbach W, Duyao M, Vonsattel J, Gusella J, Joyner A, et al. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet. 1997;17:404-10 pubmed
    ..Thus, the HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism. ..
  31. Findlay G, Smith M, Lanner F, Hsiung M, Gish G, Petsalaki E, et al. Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate. Cell. 2013;152:1008-20 pubmed publisher
    ..This optimized system ensures that PrE lineage commitment occurs in a timely and selective manner during embryogenesis. ..
  32. Xu B, Yang L, Hinton B. 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. Biol Reprod. 2013;89:48 pubmed publisher
    ..In this study we analyzed the role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of these two levels. Two mouse models were generated...
  33. Sato T, Shimazaki T, Naka H, Fukami S, Satoh Y, Okano H, et al. FRS2? regulates Erk levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells. Stem Cells. 2010;28:1661-73 pubmed publisher
    ..Studies on mutant mice of FGF receptor substrate 2? (FRS2?), a central mediator for FGF signaling, combined with FRS2? knockdown or gain-of-function experiments, allowed us ..
  34. Ong S, Goh K, Lim Y, Low B, Klint P, Claesson Welsh L, et al. Suc1-associated neurotrophic factor target (SNT) protein is a major FGF-stimulated tyrosine phosphorylated 90-kDa protein which binds to the SH2 domain of GRB2. Biochem Biophys Res Commun. 1996;225:1021-6 pubmed
    ..Tyrosine phosphorylated SNT is localised in the plasma membrane where it could form a complex with Grb2 and Sos, enabling the initiation of a novel FGF-specific signalling pathway. ..
  35. Li Y, Liu J, Hudson M, Kim S, Hatch N. FGF2 promotes Msx2 stimulated PC-1 expression via Frs2/MAPK signaling. J Cell Biochem. 2010;111:1346-58 pubmed publisher
    ..Here we show that FGF signaling promotes Msx2 transcriptional activity on the PC-1 gene promoter via the Frs2/MAPK signaling pathway...
  36. Lin X, Zhang Y, Liu L, McKeehan W, Shen Y, Song S, et al. FRS2? is essential for the fibroblast growth factor to regulate the mTOR pathway and autophagy in mouse embryonic fibroblasts. Int J Biol Sci. 2011;7:1114-21 pubmed
    ..By using the Frs2? null mouse embryonic fibroblast (MEF) in conjunction with inhibitors to multiple signaling pathways, here we ..
  37. Gross I, Bassit B, Benezra M, Licht J. Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem. 2001;276:46460-8 pubmed
    ..Sos complex to selectively uncouple growth factor signals from Ras activation and the MAP Kinase pathway. ..
  38. Chikamori M, Fujimoto J, Tokai Nishizumi N, Yamamoto T. Identification of multiple SNT-binding sites on NPM-ALK oncoprotein and their involvement in cell transformation. Oncogene. 2007;26:2950-4 pubmed
    ..This raises a possibility that SNT family proteins play significant roles in cellular transformation triggered by NPM-ALK, which though remains to be verified. ..
  39. Xie Y, Wang Y, Sun T, Wang F, Trostinskaia A, Puscheck E, et al. Six post-implantation lethal knockouts of genes for lipophilic MAPK pathway proteins are expressed in preimplantation mouse embryos and trophoblast stem cells. Mol Reprod Dev. 2005;71:1-11 pubmed
    ..These included FRS2alpha, GAB1, GRB2, SOS1, Raf-B, and Raf1...
  40. Chen P, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, et al. Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Invest. 2015;125:4514-28 pubmed publisher
    ..These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis. ..
  41. Nandi S, Gutin G, Blackwood C, Kamatkar N, Lee K, Fishell G, et al. FGF-Dependent, Context-Driven Role for FRS Adapters in the Early Telencephalon. J Neurosci. 2017;37:5690-5698 pubmed publisher
    ..Here, we used the developing mouse telencephalon as an example to study the role of the FRS adapters FRS2 and FRS3 in mediating the functions of FGFRs...
  42. Haling J, Wang F, Ginsberg M. Phosphoprotein enriched in astrocytes 15 kDa (PEA-15) reprograms growth factor signaling by inhibiting threonine phosphorylation of fibroblast receptor substrate 2alpha. Mol Biol Cell. 2010;21:664-73 pubmed publisher
    ..prevented ERK1/2 membrane recruitment and threonine phosphorylation of fibroblast receptor substrate 2alpha (FRS2alpha), a key link in fibroblast growth factor (FGF) receptor activation of ERK1/2...
  43. Murohashi M, Nakamura T, Tanaka S, Ichise T, Yoshida N, Yamamoto T, et al. An FGF4-FRS2alpha-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos. Stem Cells. 2010;28:113-21 pubmed publisher
    ..We provide evidence that FRS2alpha mediates activation of the extracellular signal-regulated progein kinase (ERK) pathway to enhance expression of ..
  44. Kameda Y, Ito M, Nishimaki T, Gotoh N. FRS2alpha is required for the separation, migration, and survival of pharyngeal-endoderm derived organs including thyroid, ultimobranchial body, parathyroid, and thymus. Dev Dyn. 2009;238:503-13 pubmed publisher
    The docking protein FRS2alpha plays an important role in fibroblast growth factor (FGF)-induced intracellular signal transduction by linking FGF receptors (FGFRs) to a variety of intracellular signaling pathways...
  45. Lundgren T, Stenqvist A, Scott R, Pawson T, Ernfors P. Cell migration by a FRS2-adaptor dependent membrane relocation of ret receptors. J Cell Biochem. 2008;104:879-94 pubmed publisher
    ..cells is elicited by the activation of specific signaling pathways initiated by the competitive recruitment of the FRS2 adaptor molecule to tyrosine 1062 (Y1062) in RET...
  46. Chen P, Qin L, Zhuang Z, Tellides G, Lax I, Schlessinger J, et al. The docking protein FRS2? is a critical regulator of VEGF receptors signaling. Proc Natl Acad Sci U S A. 2014;111:5514-9 pubmed publisher
    ..We report that the docking protein fibroblast growth factor receptor substrate 2 (FRS2?) plays a critical role in cell signaling via these receptors...
  47. Lee S, Griep A. Loss of Dlg-1 in the mouse lens impairs fibroblast growth factor receptor signaling. PLoS ONE. 2014;9:e97470 pubmed publisher
  48. Hu H, Hilton M, Tu X, Yu K, Ornitz D, Long F. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005;132:49-60 pubmed
    ..Finally Wnt7b is identified as a potential endogenous ligand regulating osteogenesis. These data support a model that integrates Hh and Wnt signaling in the regulation of osteoblast development. ..
  49. Pathania M, Wang Y, Simirskii V, Duncan M. β1-integrin controls cell fate specification in early lens development. Differentiation. 2016;92:133-147 pubmed publisher
    ..Thus, β1-integrin has an important role in fine-tuning the response of the early lens to the gradient of growth factors that regulate lens fiber cell differentiation. ..