Alternative titles; symbols
HGNC Approved Gene Symbol: FRS2
Cytogenetic location: 12q15 Genomic coordinates (GRCh38): 12:69,470,388-69,579,793 (from NCBI)
Kouhara et al. (1997) identified FRS2 as a tyrosine-phosphorylated protein that binds GRB2 (108355) in response to FGF (see 131220) stimulation. By protein purification, sequence analysis, PCR of cDNA prepared from mRNA isolated from NIH 3T3 cells, and screening of a Swiss 3T3 cell cDNA library, they isolated a full-length cDNA encoding FRS2. The deduced 508-amino acid protein has a predicted molecular mass of 56.8 kD. It contains a myristylation sequence, a phosphotyrosine-binding (PTB) domain, and 4 potential GRB2-binding sites. Northern blot analysis of adult mouse tissues detected ubiquitous expression of Frs2, with highest levels in brain, kidney, lung, ovary, and testis. SDS-PAGE showed that FRS2 migrates as doublet of 92 to 95 kD.
Gross (2016) mapped the FRS2 gene to chromosome 12q15 based on an alignment of the FRS2 sequence (GenBank AF036717) with the genomic sequence (GRCh38).
Kouhara et al. (1997) showed that FRS2 is tyrosine phosphorylated and binds to GRB2/SOS (see 182530) in response to FGF or nerve growth factor (NGF; 162030) stimulation. They determined that FRS2 is myristylated, and this modification was found to be essential for membrane localization, tyrosine phosphorylation, GRB2/SOS recruitment, and mitogen-activated protein kinase (MAPK) activation. Kouhara et al. (1997) concluded that FRS2 functions as a lipid-anchored docking protein that targets signaling molecules to the plasma membrane in response to FGF stimulation to link receptor activation with MAPK and other signaling pathways essential for cell growth and differentiation.
Using yeast 2-hybrid interaction assays, Xu et al. (1998) showed that SNT1 and SNT2 (607744) directly bind to FGFR1 (136350). A juxtamembrane segment of FGFR1 and the PTB domain of the SNTs were both necessary and sufficient for interaction in yeast and in vitro, and FGFR-mediated SNT tyrosine phosphorylation in vivo required these segments.
Lax et al. (2002) demonstrated that, in addition to tyrosine phosphorylation, FRS2A is phosphorylated by MAPK on multiple threonine residues in response to FGF stimulation or by insulin, epidermal growth factor (EGF; 131530), and platelet-derived growth factor (PDGF; see 190040), extracellular stimuli that do not induce tyrosine phosphorylation of FRS2A. Prevention of FRS2A threonine phosphorylation resulted in constitutive tyrosine phosphorylation of FRS2A in unstimulated cells and enhanced tyrosine phosphorylation of FRS2A, MAPK stimulation, cell migration, and proliferation in FGF-stimulated cells. Expression of an FRS2A mutant deficient in MAPK phosphorylation sites induced anchorage-independent cell growth and colony formation in soft agar. These experiments revealed 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.
Melillo et al. (2001) presented evidence that FRS2 couples both ligand-regulated and oncogenic forms of RET (164761) with the MAPK signaling cascade under normal biologic conditions and pathologic conditions, such as multiple endocrine neoplasias (see 171400) and papillary thyroid carcinomas (188550).
Gotoh et al. (2004) explored the role of signaling pathways downstream of Frs2 in eye development by analyzing mice with point mutations in either the 4 Grb2-binding sites or the 2 Shp2 (PTPN11; 176876)-binding sites of Frs2. Mice with mutations in the 4 Grb2-binding sites exhibited normal early eye development, whereas mice with mutations in the 2 Shp2-binding sites showed anophthalmia or microphthalmia. In severe cases, expression of Pax6 (607108) and Six3 (603714) in the lens placode and of Chx10 (142993) in the presumptive retina was greatly diminished or absent, indicating a failure of inductive signaling in both tissues. In addition, expression of Bmp4 (112262) was all but lost from the optic primordium, suggesting that FGF signaling is upstream of Bmp4 function in a pathway regulating eye development.
Yamamoto et al. (2005) showed that targeted disruption of the Shp2-binding sites in mouse Frs2a led to severe impairment in cerebral cortex development. The defect appeared to be due, at least in part, to abnormalities in intermediate progenitor cells. Fgf2 (134920)-responsive neurospheres from Frs2a mutant mice were smaller than those of wildtype mice, but mutant neural stem/progenitor cells could self-renew. These results indicated that Shp2-binding sites on Frs2a play an important role in neural stem/progenitor cell proliferation, but they are dispensable for neural stem/progenitor cell self-renewing capacity after Fgf2 stimulation.
Gotoh, N., Ito, M., Yamamoto, S., Yoshino, I., Song, N., Wang, Y., Lax, I., Schlessinger, J., Shibuya, M., Lang, R. A. Tyrosine phosphorylation sites on FRS2-alpha responsible for Shp2 recruitment are critical for induction of lens and retina. Proc. Nat. Acad. Sci. 101: 17144-17149, 2004. [PubMed: 15569927] [Full Text: https://doi.org/10.1073/pnas.0407577101]
Gross, M. B. Personal Communication. Baltimore, Md. 3/31/2016.
Kouhara, H., Hadari, Y. R., Spivak-Kroizman, T., Schilling, J., Bar-Sagi, D., Lax, I., Schlessinger, J. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89: 693-702, 1997. [PubMed: 9182757] [Full Text: https://doi.org/10.1016/s0092-8674(00)80252-4]
Lax, I., Wong, A., Lamothe, B., Lee, A., Frost, A., Hawes, J., Schlessinger, J. The docking protein FRS2-alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Molec. Cell 10: 709-719, 2002. [PubMed: 12419216] [Full Text: https://doi.org/10.1016/s1097-2765(02)00689-5]
Melillo, R. M., Santoro, M., Ong, S.-H., Billaud, M., Fusco, A., Hadari, Y. R., Schlessinger, J., Lax, I. Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Molec. Cell. Biol. 21: 4177-4187, 2001. [PubMed: 11390647] [Full Text: https://doi.org/10.1128/MCB.21.13.4177-4187.2001]
Xu, H., Lee, K. W., Goldfarb, M. Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins. J. Biol. Chem. 273: 17987-17990, 1998. [PubMed: 9660748] [Full Text: https://doi.org/10.1074/jbc.273.29.17987]
Yamamoto, S., Yoshino, I., Shimazaki, T., Murohashi, M., Hevner, R. F., Lax, I., Okano, H., Shibuya, M., Schlessinger, J., Gotoh, N. Essential role of Shp2-binding sites on FRS2-alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells. Proc. Nat. Acad. Sci. 102: 15983-15988, 2005. [PubMed: 16239343] [Full Text: https://doi.org/10.1073/pnas.0507961102]