Syndecan-4 Is Required for Thrombin-induced Migration and Proliferation in Human Vascular Smooth Muscle Cells

Rauch, Bernhard; Millette, Esther; Kenagy, Richard D.; Daum, Guenter; Fischer, Jens W.; Clowes, Alexander W.

doi:10.1074/jbc.m410848200

Cited by 64 publications

(53 citation statements)

References 30 publications

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“…To study the role of FGFR1 signaling in VSMC and to avoid the confounding effects of heparan sulfate proteoglycans on FGF receptor signaling, we developed a constitutively activated FGFR1 with mutations that abolish signaling through specific pathways. These mutants eliminate the need for FGF2 stimulation, which will abrogate FGF-mediated signaling through syndecans (32,33) and allows dissection of signaling via FGFR1. These constitutively active FGFR1 mutants reveal that the majority of ERK signaling occurs through FGFR1 interaction with FRS2, although low level ERK signaling occurred with FGFR1 K562E: ϪFRS2.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…We began with ERK activation, because it can occur after ligand binding (30) and was reported to be an early event during syndecan-1-mediated internalization (Ͻ10 min) (31). Previous studies did not indicate which site(s) on ERK became phosphorylated upon syndecan engagement.…”

Section: Mkkk Motif Mediates Basal Association With ␣-Tubulin Rapid mentioning

confidence: 99%

Molecular Mediators for Raft-dependent Endocytosis of Syndecan-1, a Highly Conserved, Multifunctional Receptor

Chen

Williams

2013

Journal of Biological Chemistry

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Background: Endocytosis via rafts remains incompletely characterized. Results: Raft-dependent endocytosis of syndecan-1 occurs in two phases, each requiring a kinase and a corresponding cytoskeletal partner. Each phase depends on MKKK, a novel, conserved motif within syndecan-1. Conclusion: These findings demonstrate the molecular choreography behind endocytosis of a raft-dependent receptor. Significance: Syndecans mediate uptake of biologically and medically important ligands.

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“…PAECs also produce factors that inhibit PASMC growth, such as nitric oxide (7), prostacyclin (8), heparin-like compounds (9)(10)(11), and xanthine oxidase (12).…”

mentioning

confidence: 99%

Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

Ochoa¹,

Baker²,

Hasak³

et al. 2008

Am J Respir Cell Mol Biol

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Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAECs) produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAECs exposed to cyclic stretch secrete proteins that inhibit PASMC growth. Media from PAECs exposed to cyclic stretch significantly inhibited PASMC growth in a time-dependent manner. Lyophilized material isolated from stretched PAEC-conditioned media significantly inhibited PASMC growth in a dose-dependent manner. This inhibition was reversed by trypsin inactivation, which is consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAECs, we used proteomic techniques and found that thrombospondin (TSP)-1, a natural antiangiogenic factor, was up-regulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1-blocking antibodies reversed conditioned media-induced inhibition of PASMC growth. Cyclic stretched PAECs secrete protein(s) that inhibit PASMC proliferation. TSP-1 may be, at least in part, responsible for this inhibition. The complete identification and understanding of the secreted proteome of stretched PAECs may lead to new insights into the pathophysiology of pulmonary vascular remodeling.

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Syndecan-4 Is Required for Thrombin-induced Migration and Proliferation in Human Vascular Smooth Muscle Cells

Cited by 64 publications

References 30 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

Molecular Mediators for Raft-dependent Endocytosis of Syndecan-1, a Highly Conserved, Multifunctional Receptor

Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

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