The Docking Protein FRS2α Is an Essential Component of Multiple Fibroblast Growth Factor Responses during Early Mouse Development

Gotoh, Noriko; Manova, Katia; Tanaka, Satoshi; Murohashi, Michiko; Hadari, Yaron R.; Lee, A.; Hamada, Y.; Hiroe, Takeshi; Ito, Masataka; Kurihara, Taisei; Nakazato, Hiroshi; Shibuya, Masabumi; Lax, Irit; Lacy, Elizabeth; Schlessinger, Joseph

doi:10.1128/mcb.25.10.4105-4116.2005

Cited by 82 publications

(80 citation statements)

References 55 publications

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“…FGF4 produced by the epiblast regulates the proliferation and maintenance of trophoblast stem cells (36). FGFR2 (37), the main FGFR in these cells, and its downstream adaptor molecule FRS2␣ (38) are essential for trophoblast stem cell renewal. FRS2␣, in particular, is required for full-fledged ERK activation in the extraembryonic ectoderm.…”

Section: Resultsmentioning

confidence: 99%

Essential role of B-Raf in ERK activation during extraembryonic development

Galabova-Kovacs

Matzen

Piazzolla

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The kinases of the Raf family have been intensively studied as activators of the mitogen-activated protein kinase kinase͞extra-cellular signal-regulated kinase (ERK) module in regulated and deregulated proliferation. Genetic evidence that Raf is required for ERK activation in vivo has been obtained in lower organisms, which express only one Raf kinase, but was hitherto lacking in mammals, which express more than one Raf kinase. Ablation of the two best studied Raf kinases, B-Raf and Raf-1, is lethal at midgestation in mice, hampering the detailed study of the essential functions of these proteins. Here, we have combined conventional and conditional gene ablation to show that B-Raf is essential for ERK activation and for vascular development in the placenta. B-Rafdeficient placentae show complete absence of phosphorylated ERK and strongly reduced HIF-1␣ and VEGF levels, whereas all these parameters are normal in Raf-1-deficient placentae. In addition, neither ERK phosphorylation nor development are affected in B-raf-deficient embryos that are born alive obtained by epiblastrestricted gene inactivation. The data demonstrate that B-Raf plays a nonredundant role in ERK activation during extraembyronic mammalian development in vivo.T he placenta is the first organ to develop during embryogenesis, and it supports the growth of the developing embryo by mediating the exchange of nutrients and wastes between the fetal and maternal circulatory systems. Placentation includes extensive angiogenesis, and reduced placental vascular development is associated with early embryonic mortality. Genetic studies have demonstrated a crucial role of VEGF, FGF, and their receptors in placental angiogenesis. In addition, the ablation of several signaling molecules operating downstream of receptor tyrosine kinases results in defects in placentation, often at the stage of labyrinth formation (1).The Raf kinases (A-Raf, B-Raf, and Raf-1) relay signals from tyrosine kinase receptors to the mitogen-activated protein kinase kinase (MEK)͞extracellular signal-regulated kinase (ERK) signaling module. Although most of the early work on the activation of the MEK͞ERK module was focused on Raf-1, evidence has accumulated that B-Raf is the main MEK kinase. Raf kinases from lower organisms (Caenorhabditis elegans lin-45 and Drosophila D-Raf ) are more similar to B-Raf than to the other two mammalian Raf kinases. Biochemical studies have indicated that B-Raf is the main MEK kinase found in fibroblast and brain lysates (2-5). Consistently, among the three Raf kinases, B-Raf binds best to MEK (6) and has the highest basal MEK kinase activity, both in vitro (7) and in fibroblasts, when expressed as a conditionally oncogenic form (8). Finally, B-Raf mutations resulting in increased MEK͞ERK activation have been discovered in a broad range of human tumors (9). All these observations hint at B-Raf as the archetypal mammalian MEK kinase, whereas Raf-1 and A-Raf have probably diverged to perform other functions. Growth-factor-stimulated ERK activation is reduced...

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Section: Resultsmentioning

confidence: 99%

Essential role of B-Raf in ERK activation during extraembryonic development

Galabova-Kovacs

Matzen

Piazzolla

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Northern blotting RNA from mouse brain and NIH3T3 cells were prepared using a standard method (Gotoh et al, 2005). Probes for mouse Frs2a and Frs2b were previously described (Gotoh et al, 2004b).…”

Section: Co-immunoprecipitation Assaysmentioning

confidence: 99%

“…It has been reported that SNT-1/FRS2a mediates multiple FGF-induced cellular responses, including stimulation of the Ras/ERK cascade and activation of phosphatidylinositol (PI)-3 kinase Ong et al, 2001). Snt-1/Frs2a-null mouse embryos show early embryonic lethality due to defects in multiple FGF responses during development, indicating that SNT-1/ FRS2a is essential for FGF signaling in vivo (Gotoh et al, 2005). Ectopic expression of SNT-2/FRS2b in Snt-1/Frs2a À/À mouse embryonic fibroblasts (MEFs) compensates for the loss of SNT-1/FRS2a in activation of ERK in response to FGF, indicating that SNT-1/ FRS2a and SNT-2/FRS2b have redundant roles in FGF signaling (Gotoh et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

Unique role of SNT-2/FRS2β/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways

et al. 2006

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The membrane-linked docking protein SNT-2/FRS2b/ FRS3 becomes tyrosine phosphorylated in response to fibroblast growth factors (FGFs) and neurotrophins and serves as a platform for recruitment of multiple signaling proteins, including Grb2 and Shp2, to FGF receptors or neurotrophin receptors. We previously reported that SNT-2 is not tyrosine phosphorylated significantly in response to epidermal growth factor (EGF) but that it inhibits ERK activation via EGF stimulation by forming a complex with ERK2. In the present report, we show that expression of SNT-2 suppressed EGF-induced cell transformation and proliferation, and expression level of SNT-2 is downregulated in cancer. The activities of the major signaling molecules in EGF receptor (EGFR) signal transduction pathways, including autophosphorylation of EGFR, were attenuated in cells expressing SNT-2 but not in cells expressing SNT-2 mutants lacking the ERK2-binding domain. Furthermore, SNT-2 constitutively bound to EGFR through the phosphotyrosine binding (PTB) domain both with and without EGF stimulation. Treatment of cells with MEK inhibitor U0126 partially restored the phosphorylation levels of MEK and EGFR in cells expressing SNT-2. On the basis of these findings, we propose a novel mechanism of negative control of EGFR tyrosine kinase activity with SNT-2 by recruiting ERK2, which is the site of negative-feedback loop from ERK, ultimately leading to inhibition of EGF-induced cell transformation and proliferation.

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“…Disruption of the Frs2␣ gene results in early embryonic lethality due to multiple defects in FGF signaling, such as defects in trophoblast stem cells that self-renew in the presence of FGF4 and defects in cell movement through the primitive streak during gastrulation (23). To elucidate the signaling pathways emanating from the Shp2-binding sites and Grb2-binding sites of FRS2␣, we generated mice carrying mutations of either the two tyrosine residues that act as the Shp2-binding sites (Frs2␣ 2F ) or the four tyrosine residues serving as the Grb2 binding sites (Frs2␣ 4F ).…”

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confidence: 99%