SNT1/FRS2 Mediates Germinal Vesicle Breakdown Induced by an Activated FGF Receptor1 in Xenopus Oocytes

Mood, Kathleen; Friesel, Robert; Daar, Ira

doi:10.1074/jbc.m203894200

Cited by 16 publications

(18 citation statements)

References 84 publications

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“…Antibody against phosphotyrosine clone 4G10 (05-321, 1:2000) was purchased from Upstate. Mouse monoclonal antibody against Xenopus transmembrane region of FGFR1 (5G11, 1:300) and rabbit polyclonal antibody against C-terminal region of FGFR1 (FB817, 1:1000) have been described previously (24).…”

Section: Methodsmentioning

confidence: 99%

FRS2 via Fibroblast Growth Factor Receptor 1 Is Required for Platelet-derived Growth Factor Receptor β-mediated Regulation of Vascular Smooth Muscle Marker Gene Expression

Chen

Simons

Friesel

2009

Journal of Biological Chemistry

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Vascular smooth muscle cells (VSMC) exhibit phenotypic plasticity and change from a quiescent contractile phenotype to a proliferative synthetic phenotype during physiological arteriogenesis and pathological conditions such as atherosclerosis and restenosis. Platelet-derived growth factor (PDGF)-BB is a potent inducer of the VSMC synthetic phenotype; however, much less is known about the role of fibroblast growth factor-2 (FGF2) in this process. Here, we show using signal transduction mutants of FGF receptor 1 (FGFR1) expressed in rat VSMC that the adaptor protein FRS2 is essential for FGFR1-mediated phenotypic modulation and downregulation of VSMC smooth muscle ␣-actin (SMA) gene expression. In addition, we show that PDGF-BB and FGF2 act synergistically to induce cell proliferation and down-regulate SMA and SM22␣ in VSMC. Furthermore, we show that PDGF-BB induces tyrosine phosphorylation of FGFR1 and that this phosphorylation is mediated by PDGF receptor-␤ (PDGFR␤), but not c-Src. We demonstrate that FRS2 co-immunoprecipitates with PDGFR␤ in a complex that requires FGFR1 and that both the extracellular and the intracellular domains of FGFR1 are required for association with PDGFR␤, whereas the cytoplasmic domain of FGFR1 is required for FRS2 association with the FGFR1-PDGFR␤ complex. Knockdown of FRS2 in VSMC by RNA interference inhibited PDGF-BB-mediated down-regulation of SMA and SM22␣ without affecting PDGF-BB mediated cell proliferation or ERK activation. Together, these data support the notion that PDGFR␤ down-regulates SMA and SM22␣ through formation of a complex that requires FGFR1 and FRS2 and prove novel insight into VSMC phenotypic plasticity. Phenotypic modulation of vascular smooth muscle cells (VSMC)3 is an important step in the development of several pathophysiological processes including atherosclerosis, restenosis, and vascular remodeling (1, 2). During these processes VSMC change from a contractile phenotype to a synthetic phenotype characterized by increased proliferation, migration, increased extracellular matrix production, and decreased expression of contractile proteins, including smooth muscle ␣-actin (SMA), SM22␣, calponin, and myosin heavy chain. Several growth factors including platelet-derived growth factor-BB (PDGF-BB), fibroblast growth factor 2 (FGF2), and thrombin have been implicated in the induction of the synthetic phenotype (3). These growth factors bind cell surface receptors and activate intracellular signaling pathways that result in changes in gene expression and cellular phenotype. Understanding the interactions between these pathways may provide insights into mechanisms of phenotypic modulation of VSMC and provide new targets for therapeutic intervention in vascular disease. Experimental evidence using various in vitro and in vivo models points to a role for FGF-FGFR in the phenotypic modulation of VSMC. FGFs and FGFRs are expressed in VSMC and are up-regulated during vascular injury and in atherosclerotic plaque formation (4 -6). Balloon injury of rat arteries led to an...

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Section: Methodsmentioning

confidence: 99%

FRS2 via Fibroblast Growth Factor Receptor 1 Is Required for Platelet-derived Growth Factor Receptor β-mediated Regulation of Vascular Smooth Muscle Marker Gene Expression

Chen

Simons

Friesel

2009

Journal of Biological Chemistry

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“…In contrast to the Met receptor, which can directly interact with Gab1 (Lock et al, 2003), the FGFR recruits Gab1 indirectly, via the binding of Grb2 to another scaffold protein known as FRS2 (Lamothe et al, 2004). Activation of the FGFR1 induces cell cycle progression, and activation of MAPK and JNK in Xenopus oocytes, which has been shown to be dependent on FRS2 and Grb2 (Browaeys-Poly et al, 2000;Carballada et al, 2001;Mood et al, 2002). To define the requirement of Gab1-dependent signals in the FGFR1-induced cell cycle transition, RNAs encoding FGFR1 and FRS2 were injected into oocytes in the presence or absence of the MBD of Gab1, and these oocytes were subsequently stimulated with 200 ng/ml basic FGF.…”

Section: Gab1 Mbd Represses Gvbd Induced By the Fgf Receptor But Notmentioning

confidence: 99%

“…Generation and characterization of the wild-type (wt) or mutants of Tpr-Met, signaling-specific variants as well as XFGFR1 and XFRS2 cDNA constructs were described previously (Fixman et al, 1996;Mood et al, 2002Mood et al, , 2006Saucier et al, 2002). For expression in Xenopus oocytes, mouse Gab1 cDNAs were subcloned into the BamH1/EcoR1 site of the pCS2 ϩ vector.…”

Section: Tpr-met and Gab1 Cdna Constructsmentioning

confidence: 99%

Gab1 Is Required for Cell Cycle Transition, Cell Proliferation, and Transformation Induced by an Oncogenic Met Receptor

Mood

Saucier

Bong

et al. 2006

MBoC

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We have shown previously that either Grb2-or Shc-mediated signaling from the oncogenic Met receptor Tpr-Met is sufficient to trigger cell cycle progression in Xenopus oocytes. However, direct binding of these adaptors to Tpr-Met is dispensable, implying that another Met binding partner mediates these responses. In this study, we show that overexpression of Grb2-associated binder 1 (Gab1) promotes cell cycle progression when Tpr-Met is expressed at suboptimal levels. This response requires that Gab1 possess an intact Met-binding motif, the pleckstrin homology domain, and the binding sites for phosphatidylinositol 3-kinase and tyrosine phosphatase SHP-2, but not the Grb2 and CrkII/phospholipase C␥ binding sites. Importantly, we establish that Gab1-mediated signals are critical for cell cycle transition promoted by the oncogenic Met and fibroblast growth factor receptors, but not by progesterone, the natural inducer of cell cycle transition in Xenopus oocytes. Moreover, Gab1 is essential for Tpr-Met-mediated morphological transformation and proliferation of fibroblasts. This study provides the first evidence that Gab1 is a key binding partner of the Met receptor for induction of cell cycle progression, proliferation, and oncogenic morphological transformation. This study identifies Gab1 and its associated signaling partners as potential therapeutic targets to impair proliferation or transformation of cancer cells in human malignancies harboring a deregulated Met receptor.

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“…Antibodies against EGFR and myc-Tag were purchased from Santa Cruz. Mouse monoclonal antibody against Xenopus FGFR1 (5G11) has been described previously [19]. For statistical analysis, the intensity of individual band in a given Western blot analysis was quantified using Image Quant analyzing software (Molecular Dynamics) and normalization to β-tubulin.…”

Section: Methodsmentioning

confidence: 99%

FGFR1 forms an FRS2-dependent complex with mTOR to regulate smooth muscle marker gene expression

Chen

Friesel

2009

Biochemical and Biophysical Research Communications

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Vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic phenotype in human cardiovascular disease such as atherosclerosis and restenosis after angioplasty. VSMCs show reduced expression of contractile proteins and are capable of responding to mitogens by increasing expression of growth factor receptors. Fibroblast growth factor receptor-1 (FGFR1) signaling is one of several signaling pathways involved in this VSMC phenotypic switching. The aim of the present study was to examine the signaling pathway downstream of FGFR1 in the regulation of SM marker gene expression. We found that FGFR1 activated Akt/mTOR pathway and that the mTOR inhibitor rapamycin partially reversed FGFR1-mediated downregulated SM marker gene expression. Furthermore, we showed that mTOR forms a multi-protein complex with FGFR1 in VSMCs. These findings provide novel information for future development of therapeutic strategies for the treatment of human cardiovascular disease.

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SNT1/FRS2 Mediates Germinal Vesicle Breakdown Induced by an Activated FGF Receptor1 in Xenopus Oocytes

Cited by 16 publications

References 84 publications

FRS2 via Fibroblast Growth Factor Receptor 1 Is Required for Platelet-derived Growth Factor Receptor β-mediated Regulation of Vascular Smooth Muscle Marker Gene Expression

FRS2 via Fibroblast Growth Factor Receptor 1 Is Required for Platelet-derived Growth Factor Receptor β-mediated Regulation of Vascular Smooth Muscle Marker Gene Expression

Gab1 Is Required for Cell Cycle Transition, Cell Proliferation, and Transformation Induced by an Oncogenic Met Receptor

FGFR1 forms an FRS2-dependent complex with mTOR to regulate smooth muscle marker gene expression

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