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FRS2  -  fibroblast growth factor receptor substrate 2

Homo sapiens

Synonyms: FGFR substrate 2, FGFR-signaling adaptor SNT, FRS2A, FRS2alpha, Fibroblast growth factor receptor substrate 2, ...
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Disease relevance of FRS2

  • These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas [1].
  • We found that the L5 VRT produced rapid (24 h after transection), robust and prolonged (56 days) bilateral mechanical allodynia, to a similar extent to that in rats with L5 spinal nerve transection (L5 SNT), cold allodynia and short-term thermal hyperalgesia (14 days) [2].
  • In addition, mRNA encoding tumor protein D52 was overexpressed in 60% of breast cancer specimens, while transcripts encoding SNT-1 signal adaptor protein were downregulated in 70% of these cases [3].

High impact information on FRS2

  • 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 [4].
  • We find that FRS2 is myristylated and that this modification is essential for membrane localization, tyrosine phosphorylation, Grb2/Sos recruitment, and MAPK activation [4].
  • These experiments reveal a novel MAPK-mediated, negative feedback mechanism for control of signaling pathways that are dependent on FRS2 and a mechanism for heterologous control of signaling via FGF receptors [5].
  • SNT adaptor proteins transduce activation of fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs) to common signaling targets [6].
  • The SNT-1 phosphotyrosine binding (PTB) domain recognizes activated TRKs at a canonical NPXpY motif and, atypically, binds to nonphosphorylated FGFRs in a region lacking tyrosine or asparagine [6].

Biological context of FRS2


Anatomical context of FRS2


Associations of FRS2 with chemical compounds


Physical interactions of FRS2

  • Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF receptors [7].
  • In this report, we demonstrate that FRS2 forms a complex with the N-terminal SH2 domain of the protein tyrosine phosphatase Shp2 in response to FGF stimulation [19].
  • Here we show by isothermal titration calorimetry that the FRS2alpha PTB domain binding to peptides derived from TRKs or FGFR is thermodynamically different [14].

Enzymatic interactions of FRS2


Regulatory relationships of FRS2

  • Our findings support a broader role of FRS2 in EGFR-controlled signaling pathways in A-431 cells and provide insight into a molecular mechanism for ligand-stimulated feedback regulation with FRS2 as a central regulatory switch point [20].
  • BDNF induces phosphorylation of FRS2 [9].
  • Notably, tyrosine phosphorylation of FRS2 is enhanced when ERK1/2 activation is inhibited after both EGF and FGF stimulation [20].
  • Phosphorylation by ectopic FGFR1 that promotes malignancy was much more intense and yielded a phosphorylated 85-kDa SNT1 [24].
  • However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins [1].

Other interactions of FRS2

  • This involves the direct interaction of the FRS2 PTB domain with the EGFR and results in a significantly altered mobility of FRS2 in SDS-PAGE which is also observed in FGF stimulated cells [20].
  • The ability of FRS2 to recruit cell-signaling proteins to the cell is significant because it provides a mechanism for enhancing the repertoire of VEGF-induced signaling pathways [11].
  • Now, we have intriguing data that indicates BDNF induces association of the SH2 domain containing protein tyrosine phosphatase, Shp2, with FRS2 [9].
  • SNT/FRS2 is a lipid anchored docking protein that contains an amino-terminal myristylation signal, followed by a phosphotyrosine-binding (PTB) domain and a carboxy-terminal region with multiple tyrosine residues [10].
  • Here we provide evidence that FRS2 can also play a role in epidermal growth factor (EGF) signaling [20].

Analytical, diagnostic and therapeutic context of FRS2

  • Genomic organization and comparative sequence analysis of the mouse and human FRS2, FRS3 genes [25].
  • To assay potential differences in their patterns of expression, RT-PCR analysis was used to assay FRS2 and FRS3 expression in the developing embryo and neural tube (NT) during the time of neurogenesis [25].
  • Quantitative evaluation of SNT in biological material is currently hindered by many methodological problems [26].


  1. Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Melillo, R.M., Santoro, M., Ong, S.H., Billaud, M., Fusco, A., Hadari, Y.R., Schlessinger, J., Lax, I. Mol. Cell. Biol. (2001) [Pubmed]
  2. Effect of lumbar 5 ventral root transection on pain behaviors: a novel rat model for neuropathic pain without axotomy of primary sensory neurons. Li, L., Xian, C.J., Zhong, J.H., Zhou, X.F. Exp. Neurol. (2002) [Pubmed]
  3. Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. Scanlan, M.J., Gout, I., Gordon, C.M., Williamson, B., Stockert, E., Gure, A.O., Jäger, D., Chen, Y.T., Mackay, A., O'Hare, M.J., Old, L.J. Cancer Immun. (2001) [Pubmed]
  4. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Kouhara, H., Hadari, Y.R., Spivak-Kroizman, T., Schilling, J., Bar-Sagi, D., Lax, I., Schlessinger, J. Cell (1997) [Pubmed]
  5. The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Lax, I., Wong, A., Lamothe, B., Lee, A., Frost, A., Hawes, J., Schlessinger, J. Mol. Cell (2002) [Pubmed]
  6. Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. Dhalluin, C., Yan, K.S., Plotnikova, O., Lee, K.W., Zeng, L., Kuti, M., Mujtaba, S., Goldfarb, M.P., Zhou, M.M. Mol. Cell (2000) [Pubmed]
  7. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Ong, S.H., Guy, G.R., Hadari, Y.R., Laks, S., Gotoh, N., Schlessinger, J., Lax, I. Mol. Cell. Biol. (2000) [Pubmed]
  8. A novel type I fibroblast growth factor receptor activates mitogenic signaling in the absence of detectable tyrosine phosphorylation of FRS2. Lopez, M.E., Korc, M. J. Biol. Chem. (2000) [Pubmed]
  9. The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. Easton, J.B., Royer, A.R., Middlemas, D.S. J. Neurochem. (2006) [Pubmed]
  10. Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. Kurokawa, K., Iwashita, T., Murakami, H., Hayashi, H., Kawai, K., Takahashi, M. Oncogene (2001) [Pubmed]
  11. Fibroblast growth factor receptor substrate 2 participates in vascular endothelial growth factor-induced signaling. Stoletov, K.V., Ratcliffe, K.E., Terman, B.I. FASEB J. (2002) [Pubmed]
  12. SNT1/FRS2 mediates germinal vesicle breakdown induced by an activated FGF receptor1 in Xenopus oocytes. Mood, K., Friesel, R., Daar, I.O. J. Biol. Chem. (2002) [Pubmed]
  13. Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling. Lim, Y.P., Low, B.C., Lim, J., Wong, E.S., Guy, G.R. J. Biol. Chem. (1999) [Pubmed]
  14. FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. Yan, K.S., Kuti, M., Yan, S., Mujtaba, S., Farooq, A., Goldfarb, M.P., Zhou, M.M. J. Biol. Chem. (2002) [Pubmed]
  15. 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. Krejci, P., Masri, B., Salazar, L., Farrington-Rock, C., Prats, H., Thompson, L.M., Wilcox, W.R. J. Biol. Chem. (2007) [Pubmed]
  16. Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. Moffa, A.B., Tannheimer, S.L., Ethier, S.P. Mol. Cancer Res. (2004) [Pubmed]
  17. Fibroblast growth factor receptor 1 (FGFR1) tyrosine phosphorylation regulates binding of FGFR substrate 2alpha (FRS2alpha) but not FRS2 to the receptor. Zhang, Y., McKeehan, K., Lin, Y., Zhang, J., Wang, F. Mol. Endocrinol. (2008) [Pubmed]
  18. Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform. Cha, J.Y., Maddileti, S., Mitin, N., Harden, T.K., Der, C.J. J. Biol. Chem. (2009) [Pubmed]
  19. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Hadari, Y.R., Kouhara, H., Lax, I., Schlessinger, J. Mol. Cell. Biol. (1998) [Pubmed]
  20. EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2. Wu, Y., Chen, Z., Ullrich, A. Biol. Chem. (2003) [Pubmed]
  21. The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. Meakin, S.O., MacDonald, J.I., Gryz, E.A., Kubu, C.J., Verdi, J.M. J. Biol. Chem. (1999) [Pubmed]
  22. Potential involvement of FRS2 in insulin signaling. Delahaye, L., Rocchi, S., Van Obberghen, E. Endocrinology (2000) [Pubmed]
  23. 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. Manuvakhova, M., Thottassery, J.V., Hays, S., Qu, Z., Rentz, S.S., Westbrook, L., Kern, F.G. Oncogene (2006) [Pubmed]
  24. Cell- and receptor isotype-specific phosphorylation of SNT1 by fibroblast growth factor receptor tyrosine kinases. Wang, F. In Vitro Cell. Dev. Biol. Anim. (2002) [Pubmed]
  25. Genomic organization and comparative sequence analysis of the mouse and human FRS2, FRS3 genes. Zhou, L., McDougall, K., Kubu, C.J., Verdi, J.M., Meakin, S.O. Mol. Biol. Rep. (2003) [Pubmed]
  26. Quantitative evaluation of SNT in biological material is currently hindered by many methodological problems. Włodek, L. Clin. Chim. Acta (2005) [Pubmed]
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