Sprouty Genes Are Expressed in Osteoblasts and Inhibit Fibroblast Growth Factor-Mediated Osteoblast Responses

Yang, Xuehui; Webster, J. B.; Коваленко, Д. В.; Nadeau, Robert J.; Zubanova, Olga; Chen, P.-Y.; Friesel, Robert

doi:10.1007/s00223-005-0231-4

Cited by 22 publications

(20 citation statements)

References 57 publications

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“…GST Pulldown Assays-All of the GST-fused proteins were purified from Escherichia coli as described previously (25). For pulldown assays, the cells were rinsed once with PBS and lysed with the HNTG lysis buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl 2 , 1.0 mM EGTA, 1 mM sodium orthovanadate, 1 mM sodium fluoride, and EDTA-free protease inhibitor mixture).…”

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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“…This effect is related to increased EGFR and PDGFRα expression and signaling induced by activated FGFR2 mutations, an effect which is mediated by both PKCα-mediated AP-1 transcriptional activation and a posttranscriptional mechanism involving Sprouty2 (Spry2). Spry2 acts as a feedback inhibitor of FGF-induced osteoblast response (Yang et al, 2006). FGFR2 activating mutations in osteoblasts promote the CblSpry2 interaction, which sequesters Cbl away from the EGFR, thereby impeding EGFR degradation and increasing EGFR abundance and signaling (Miraoui et al, 2010).…”

Section: Novel Aspects Of Fgf/fgfr Signaling In the Control Of Osteobmentioning

confidence: 99%

Fibroblast growth factor signaling controlling bone formation: An update

Marie

2012

Gene

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“…The Sprouty (Spry) family of proteins was originally identified as feedback inhibitors of fibroblast growth factor receptor signaling [17–19] and subsequent studies showed that other RTK signaling pathways such as VEGF are also inhibited by Spry [20–22]. Four mammalian Spry genes have been identified, and all of them are expressed in endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Sprouty4 regulates endothelial cell migration via modulating integrin β3 stability through c-Src

Gong

Yang

et al. 2013

Angiogenesis

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Angiogenesis is mediated by signaling through receptor tyrosine kinases (RTKs), Src family kinases and adhesion receptors such as integrins, yet the mechanism how these signaling pathways regulate one another remains incompletely understood. The RTK modulator, Sprouty4 (Spry4) inhibits endothelial cell functions and angiogenesis, but the mechanisms remain to be fully elucidated. In this study, we demonstrate that Spry4 regulates angiogenesis in part by regulating endothelial cell migration. Overexpression of Spry4 in human endothelial cells inhibited migration and adhesion on vitronectin (VTN), whereas knockdown of Spry4 enhanced these behaviors. These activities were shown to be c-Src-dependent and Ras-independent. Spry4 disrupted the crosstalk between vascular endothelial growth factor-2 and integrin αVβ3, the receptor for VTN. Spry4 overexpression resulted in decreased integrin β3 protein levels in a post-transcriptional manner in part by modulating its tyrosine phosphorylation by c-Src. Conversely, knockdown of Spry4 resulted in increased integrin β3 protein levels and tyrosine phosphorylation. Moreover, in vivo analysis revealed that Spry4 regulated integrin β3 levels in murine embryos and yolk sacs. Our findings identify an unanticipated role for Spry4 in regulating c-Src activity and integrin β3 protein levels, which contributes to the regulation of migration and adhesion of endothelial cells. Thus, targeting Spry4 may be exploited as a target in anti-angiogenesis therapies.

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Sprouty Genes Are Expressed in Osteoblasts and Inhibit Fibroblast Growth Factor-Mediated Osteoblast Responses

Cited by 22 publications

References 57 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

Fibroblast growth factor signaling controlling bone formation: An update

Sprouty4 regulates endothelial cell migration via modulating integrin β3 stability through c-Src

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